Phytomedicine Plus 2 (2022) 100249

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Phytomedicine Plus
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“Endophytes: an unexplored treasure to combat Multidrug resistance”

Purvashi Pasrija 1, a, Meetali Girdhar 1, a, Mukesh Kumar a, Shivani Arora b, Anju Katyal a, *
a
Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, India
b
Clemson University, Clemson, SC, USA

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Multidrug resistance (MDR) in microorganisms has culminated in major health crisis globally and
Multidrug resistance accounts for approximately 700,000 morbidities every year. Recently, there has been a surge towards re-
Endophytes discovering medieval treatment strategies to develop novel therapeutic approaches against MDR pathogens.
Antibiotics
Exploring the potential of plant based compounds or isolates from plant-associated microbes for the treatment of
Secondary metabolites
Medicinal plants
these infections is being tried. One unexplored domain in this context is endophytes. Endophytes are endo­
symbiotic microorganisms residing in the inner plant tissues and promoting plant development in various ways.
They are known to contribute to the medicinal properties of plants with ethnobotanical histories, produce potent
hydrolytic enzymes which prevent host invasion by pathogens, insects, or nematodes, and stimulate plant’s
defense system. In some cases, secondary metabolites produced by endophytes are similar to that of the host
plant, making them an equally efficient candidate for drug development. Thus, these secondary metabolites
might hold immense unexplored potential to treat MDR infections in humans and could manifest as an asset.
Hypothesis: Despite the advances in utilization of endophytes in different domains, we lack a complete under­
standing of their potential as anti-microbial agents and their mode of action against MDR pathogens. This limits
the development and utilization of endophytes as potential drug candidates. Thus, this review highlights the
current global scenario of MDR and aims to provide a detailed analysis of secondary metabolites from endo­
phytes, especially from those growing on medicinal plants for their potential antimicrobial activity. Furthermore,
the literature has been thoroughly reviewed to elucidate the potential mechanism of action of endophytes,
providing a foundation for future research and in-vivo studies.
Methods: A systematic online search was conducted until November 2021 through four scientific databases
(PubMed, Google Scholar, Scopus, and PubChem). The articles evaluating the bioactivities of endophytes present
on medicinal plants against multidrug resistant microorganisms were considered for the review and the period of
study was delimited to literature reported between 2010 to 2021.
Results: The first literature search resulted in 72,400 articles. Further, the search was narrowed down based on
the activity of endophytes only against MDR organisms and on the basis of inclusion criteria, yielding 22,250
articles. Out of these, 10,720 articles met the inclusion criteria. Approximately 350 articles were selected for
thorough literature review and 100 articles with highest cite score and relevant information were included in this
review. Our study explored the hidden potential of endophytes as antimicrobial agents and found several can­
didates that could be utilized in treatment of MDR infections in humans.
Conclusion: High availability and low maintenance of endophytes, along with their antimicrobial potential makes
them highly applicative pharmaceutical candidates towards the concerns of the “post-antibiotic era” that the
humans have approached.

Fleming, the incessant use of antibiotics for treating infections both in

humans and animals as well as for agricultural use paved way for an
1. Introduction
unpleasant consequence: Multidrug Resistance (MDR). Due to insuffi­
cient knowledge about the unique characteristics and the possibilities of
Nearly two decades after the discovery of penicillin by Sir Alexander

* Corresponding author at: Prof. Anju Katyal, Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi, New Delhi, 110007, India, Tel.:
+919868896567
E-mail address: anju_katyal@yahoo.com (A. Katyal).
1
These authors contributed equally.

https://doi.org/10.1016/j.phyplu.2022.100249

Available online 28 February 2022

2667-0313/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
P. Pasrija et al.
Abbreviations
MDR Multidrug Resistance
MRSA Methicillin-resistant Staphylococcus aureus
VRE Vancomycin-resistant Enterococci
M. tb Mycobacterium tuberculosis
XDR-TB Extensively drug resistant Tuberculosis
CDC Center for Disease Control and Prevention
NAD Nicotinamide adenine dinucleotide
MTCC Microbial Type Culture Collection
MIC Minimum Inhibitory Concentration
IC 50 Half Maximal Inhibitory Concentration
ATCC American Type Culture Collection
resistance, antibiotics were perceived as “magic bullets” that could be
consumed without the fear of probable affliction and side effects (Lax­
minarayan et al., 2013). These factors have led to numerous epidemics
worldwide caused by resistant pathogens such as methicillin-resistant
Staphylococcus aureus (MRSA), vancomycin-resistant enterococci
(VRE), drug-resistant Vibrio cholerae, multidrug and extensively
drug-resistant tuberculosis (M/XDR-TB), which were earlier confined to
hospital/s and other healthcare settings (Monowar et al., 2018).
Alarmingly, the resistance rates for MRSA, VRE, and MDR-TB stand at
97%, 59%, and 52%, respectively (CDC, 2019). Furthermore, the rate of
resistance to ciprofloxacin—used for treating urinary tract infec­
tions—has increased by 92.9% in some countries. Strategies evolved by
these microorganisms for gaining resistance and for decreasing the ef­
ficacy of conventional antibiotics include compromised efflux mecha­
nisms which pump the drugs out of the cell, enzymatic alterations that
break down or modify the antibiotics, mutated drug targets, decreased
cell membrane permeability, lipopolysaccharide modifications, and
formation of biofilms (Blair et al., 2015; Redgrave et al., 2014; Olaitan
et al., 2014; Li and Webster, 2018). The limited availability of effective
treatment strategies for MDR at present has increased the global disease
burden leading to higher mortality rates, longer durations of illness, and
sky-rocketing treatment costs. Furthermore, MDR has also resulted in
increased virulence of the resistant strains, which is highly transmissible
to other strains by horizontal gene transfer (Davies and Davies, 2010).
The increasing resistance and the risk of treatment failure has emphas­
ised the need for discovering novel therapeutic compounds that can
prove to be the “game changers” in this fight against MDR. In this aspect,
endophytes have been reported to harbour enormous potential as anti­
microbial agents and thus can be established as successful biocontrol
candidates against drug-resistant pathogens. Endophytes are endosym­
biotic microorganisms synergistic and symbiotic to their hosts and
residing in the inner tissues of various plant organs such as roots, leaves,
stems, flowers, fruits, and seeds. They are considered as a good source of
numerous biologically active compounds with antimicrobial, immuno­
modulatory, insecticidal, antioxidant, and growth promoting properties
(Strobel, 2018). Further, they protect the host against phytopathogens
by secreting metabolites such as alkaloids, steroids, terpenoids, glyco­
sides, quinones, lactones, and isocoumarins, help in faster growth by
production of phytohormones, and in return derive nutrition from the
host (Kaul et al., 2012). They are also known to be the producers of
biosurfactant molecules which can be used for replacing chemical in­
secticides and pesticides for controlling plant pathogens (Adnan et al.,
2018). Thus, this review revisits the medieval treatment strategies and
discusses the potential of various endophytes in treating drug resistant
microbial infections.
2. Methodology
To retrieve literature for this review, four scientific databases were
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Phytomedicine Plus 2 (2022) 100249
used: Google Scholar, PubMed, PubChem, and Scopus. Keywords used
for the search included “Endophytes antimicrobial activity,” “endo­
phytes on medicinal plants and their antimicrobial activity,” “endo­
phytes and their antimicrobial activity against multidrug resistant
organisms,” “multidrug resistance,” “multidrug resistant organisms,”
“medicinal plants and their metabolites,” “mechanism of action of en­
dophytes,” “endophytes in-vivo studies,” “side effects of utilizing endo­
phytes,” and “toxicity of endophytes.” The inclusion criteria was set as
follows: study period: 2010 to 2021; source of endophytes: medicinal
plants; reported activity against: MDR microorganisms; and article
language: English. At initial search, 72,400 articles were yielded, which
were narrowed down to 22,250 based on the above-mentioned inclusion
criteria. Finally, a total of 100 articles based on highest cite score and
relevant information were thoroughly analyzed and included in this
review.
3. Current Global Scenario of MDR
Multidrug resistance is the tendency of a microorganism to resist the
action of a particular drug despite being susceptible to it earlier, leading
to escalated rates of illness and mortality (Tanwar et al., 2014). The list
of MDR microbes not only includes human pathogens but also zoonic
bacteria, veterinary pathogens, as well as plant pathogens (Fodor et al.,
2020). It has been estimated that out of 100,000–200,000 tonnes of
antibiotics produced annually, the highest portion goes to the agricul­
ture, horticulture, and veterinary services (Laxminarayan et al., 2013).
The Center for Disease Control and Prevention (CDC) has enlisted
various pathogenic bacteria and fungi, categorizing them into urgent,
serious, and concerning based on the hazard level (CDC, 2019). The
serious concern about the treatment failure due to these drug resistant
strains encompasses the most vulnerable population including immu­
nocompromised people especially neonates and those undergoing can­
cer chemotherapy or dialysis for end stage renal disease. Patients
suffering from rheumatoid arthritis or have either undergone complex
surgeries or organ transplants also stand at a high risk of infection (CDC,
2019).
Antibiotic resistance has emerged as a global threat with USA
emerging as the most affected with 2.8 million cases and 35,000 deaths
followed by Europe with 33,000 deaths (World Health Organization,
2019). A recent report accounted the percentage of infections due to
resistant organisms in South-East Asia, Western-Pacific region, and Af­
rica to be 18, 12, and 6% respectively. In developing nations like India,
there is an uncontrolled use of antibiotics primarily due to the avail­
ability of cheaper over the counter drugs as well as environment and
food polluted by these agents, resulting in high number of resistant in­
fections related mortalities per year. It has been estimated that by 2050,
MDR infections would claim about 10 million lives per year (Tagliaferri
et al., 2020).
4. Strategies adopted by microorganisms to evade current
treatment regimens
The term “drug resistance” is used to imply that the microorganism
can continue to replicate in a given concentration of a drug and is
exclusively related to the concentration of drug (Kester and Fortune,
2014). Over the decades, bacteria have evolved various physiological
and genetic mechanisms to achieve this resistance and reproduce even in
the presence of high concentrations of drug/s but have been counter­
acted by certain endophytes (Table 2). One such mechanism is the
upregulation of multidrug efflux pumps for regulating the internal
environment by removing toxic substances (Cohen et al., 2013; Soto,
2013). Mycobacterium tuberculosis (M.tb) is known to contain various
efflux pumps one of which is the ATP-binding cassette (ABC) transporter
responsible for conferring resistance to beta-lactam antibiotics (da Silva
et al., 2011). Another strategy is acquisition of mutations leading to
alterations in drug targets (Andersson and Hughes, 2010). An example
P. Pasrija et al.
of this is Neisseria gonorrhoeae, the causative organism of gonorrhoea
disease. Mutations leading to changes in the amino acid sequence of
proteins have been identified in regions of gyrA and parC contributing to
fluoroquinolone resistance whereas macrolide resistance is caused by
mutations in the 23S rRNA (Yahara et al., 2018). Horizontal gene
transfer through transduction, transformation, or conjugation, is
another means of acquiring resistance adopted by bacteria (Hughes and
Andersson, 2015). The widespread use of methicillin has led to the
evolution of methicillin-resistant strains too, which are causing conse­
quential skin infections worldwide. This resistance can be accounted to
the presence of a mobile genetic cassette called staphylococcal cassette
chromosome mec (SSCmec) which contains a methicillin resistance gene
(mecA) acquired by conjugation from related species. Methicillin resis­
tance gene codes for a peptidoglycan binding enzyme (methicillin-re­
sistant penicillin binding enzyme) involved in the cross linking of
peptidoglycan in the bacterial cell wall and reduces the affinity for
beta-lactam antibiotics, thereby rendering these antibiotics ineffective
(Harkins et al., 2017). Furthermore, production of antibiotic deactivat­
ing enzymes like beta-lactamases, aminoglycoside-modifying enzymes,
and chloramphenicol acetyltransferases have been a major contributor
to MDR (Giedraitiene et al., 2011).
Other mechanisms of acquiring resistance include the presence of
conjugative and mobile transposons and gene substitutions. For
example, insertion of gene ermB in transposon 5398 (Tn 5398) drives
clindamycin resistance in Clostridium difficile (Ramírez-Vargas et al.,
2017) and macrolides used for treating Campylobacter spp. have been
rendered ineffective because of 23S rRNA gene substitutions (Bollinger
and Kathariou, 2017).
5. Assessing Medieval Treatment strategies
Plant-based traditional medicines for treatment of several ailments
have been used since prehistoric times in countries like India, China,
Brazil, and Iran. According to the WHO, about 80% of the people still
rely on medicinal herbs as remedies for their illness. Different plant parts
like Azadirachta indica A. Juss., Ocimum tenuiflorum L., Curcuma longa L.,
Zingiber officinale Roscoe, and Withania somnifera (L.) Dunal have been of
great significance because of their anti-inflammatory and anti-microbial
properties (Jamuna et al., 2013). Traditional medicines are in the
limelight since last two decades because of the synergistic effects of
various plants preventing the likelihood of development of genetic
resistance by the microbes (Ngo et al., 2013). Additionally, there are
none or few side effects compared to those of the conventional antibi­
otics. But the semisynthetic and synthetic “low cost” substitutes of the
industrial era along with the constraints like unavailability of cultivable
land, environmental competence of plants, and seasonal preference have
deterred their use. Thus, exploring novel antimicrobials with high effi­
ciency, low-maintenance, and green synthesis methods and screening
medicinal plants and their associated microbiome to derive potential
biocontrol agents has become an essential requirement for counteracting
the rapidly rising MDR (Ramesh et al., 2017; Desale and Bodhankar,
2013).
6. Secondary metabolites and their uses
Plants are not only a source of minerals and primary metabolites, but
also secondary metabolites including flavonoids, alkaloids, saponins,
terpenoids, phenolics, and lipids with immense therapeutic value
(Sivasankaridevi et al., 2013). These phytochemicals produces by plants
are directly or indirectly linked to the endophytic organisms and their
interactions with the host plant (Egamberdieva et al., 2017). Unlike
primary metabolites, secondary metabolites are organic compounds
which are not directly linked with growth and development of an or­
ganism but are essential for plant defences as well as adaptation of plants
to their environment (Tiwari and Rana, 2015). Terpenoids are a family
of polymeric isoprene derivatives essential for adaptation to biotic and
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Phytomedicine Plus 2 (2022) 100249
abiotic stressors as well as plant-plant interaction and attracting polli­
nators. They possess anti-hypertensive and insecticidal properties
(Kabera et al., 2014). Alkaloids are a group of nitrogen-containing cyclic
compounds serving as the scaffold for antibiotics such as metronidazole
and quinolones (Cushnie et al., 2014). Produced majorly by angio­
sperms, these metabolites have been used as analgesics, antispasmodics,
and as poisons (Roy, 2017). Berberine, an isoquinoline alkaloid pro­
duced by Berberis vulgaris L. is a potent therapeutic compound for
treating multiple sclerosis (Imenshahidi and Hosseinzadeh, 2016). Sa­
ponins are steroid and triterpenoid glycosides important for responding
to external stimuli as well as phytoprotection (Faizal and Geelen, 2013).
They exhibit excellent anticancer and anti-inflammatory properties and
are even used as adjuvants in vaccines (Man et al., 2010; Augustin et al.,
2011). Produced by bryophytes, plant phenolics are compounds con­
taining aromatic rings with one or more hydroxyl groups found abun­
dantly in vegetables, fruits, tea, coffee, olive, and legumes (Cheynier
et al., 2013; Dai and Mumper, 2010). They are essential for protecting
the plant against ultraviolet radiation or invasion against pathogens and
contribute to the plant’s colour. Curcumin, a phenolic compound ob­
tained from Curcuma longa L. has a wide range of remedial properties
like immunomodulation, anti-carcinogenicity, hepatoprotection as well
as inhibition of inflammatory cytokines (Sun et al., 2018). Phenolics
include phenolic acids, flavonoids, tannins, and lignans. Flavonoids
consist of a polyphenolic structure synthesized by the polypropanoid
pathway (Ghasemzadeh and Ghasemzadeh, 2011). They have been
known to be efficient antioxidants, anticancer, antibacterial, and car­
dioprotective agents as well as protect the skin from UV damage
(Tungmunnithum et al., 2018). Tannins are large polyphenolic com­
pounds with hydroxyl and carboxyl groups which impart astringent
properties to the plant and enhance the immune system in humans
whereas lignans are dimericphenylpropanoids with antimicrobial
properties (Chandra et al., 2017). The chamomile genus Matricaria is a
reservoir of compounds like volatile terpenoids, sesquiterpene lactones,
and phenolic compounds and is used widely for the treatment of
gastrointestinal disorders, inflammation, and bacterial infections
(Sharifi-Rad et al., 2018).
7. Endophytes: The unexplored treasure
Plant microbiome greatly influences plant physiology by promoting
growth, nutrient accession, and tolerance to stress. Endophytes are
ubiquitous microorganisms residing in the inner tissues of different
plant parts forming a mutualistic relationship with the host without
causing any disease-like symptoms (Passari et al., 2015). It is believed
that they secrete secondary metabolites that confer greater evolutionary
fitness and consequent survival to the host plant by providing protection
against pathogens. One mechanism includes production of potent hy­
drolytic enzymes preventing the invasion of host by any pathogen, in­
sect, or nematode and stimulation of the plant’s defence system to evade
infections (Martinez-Klimova et al., 2017). It has been well studied that
endophytes also contribute to the medicinal properties of plants with
ethnobotanical histories. In some cases, the secondary metabolite pro­
duced by the endophyte is similar to that of the host plant, making it an
equally efficient candidate for drug development. In the family Tax­
aceae, the endophyte Pestalotiopsis microspora is known to produce the
plant host metabolite, torreyanic acid, a potent anticancer compound
(Ludwig-Müller, 2015). Eupenicillium parvum, an endophytic fungus of
Azadirachita indica A. Juss has been found to produce the insecticides
azadirachitin A and B which were earlier thought to be produced only by
the neem tree (Kusari et al., 2012). The production of bioactive com­
pound gentiopicrin with chlorotic, anti-hepatotoxic, antifungal, and
anti-inflammatory activities by fungal strain QJ18 which was initially
extracted from the host medicinal plant Gentiana macrophylla Pall,
further substantiates the use of endophytes to develop novel treatment
strategies in future (Kumar et al., 2014).
P. Pasrija et al. Phytomedicine Plus 2 (2022) 100249

Fig. 1. Bacterial and fungal endophytes and their bioactive metabolites.

Fig. 2. Flow diagram summarizing the mechanism of action of endophytes against drug-resistant microorganisms.

7.1. Endophytes as a potent source of antibiotics
Phylum Ascomycota and Actinobacteria represent the two major
classes of endophytes responsible for the production of antibiotics. The
secondary metabolites from endophytes can prove to be promising
candidates for pharmaceutical and agricultural use because of their anti-
microbial, anti-inflammatory, anti-carcinogenic, and antioxidant
properties (El-Deeb et al., 2013). An example of this is Taxol extracted
from Pacific yew tree Taxus brevifolia Nutt., which is currently being sold
under the generic name “paclitaxel” for treating ovarian, breast, and
lung cancer as well as Kaposi’s sarcoma (Weaver, 2014). The efficient
use of endophytic metabolites as therapeutic drugs is still in infancy and
needs to be explored further so as to prevent the dissemination of MDR
pathogens and avert the danger of future pandemics.

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P. Pasrija et al. Phytomedicine Plus 2 (2022) 100249

Table 1
Multi-drug resistant Pathogens, their mechanism of acquiring resistance and the endophytes along with their sources, proven to be effective against these pathogens.
PATHOGEN MECHANISM OF ACQUIRING RESISTANCE ENDOPHYTES PROVEN TO BE PLANT(S) FROM REFERENCES
SOURCES OF BIOCONTROL WHICH ENDOPHYTE IS
ACTIVITY AGAINST THE EXTRACTED
PATHOGEN

MDR Mycobacterium De novo acquisition of mutations in katG gene, rpoB and Streptomyces scabrisporus Amphipterygium (Manson et al., 2017; Comas
tuberculosis non-synonymous mutations in genes rpoA and rpoC, adstringens (Schltdl.) et al., 2012; Trenado-Uribe
mutations in “quinolone-resistance determining Standl. et al., 2018)
region” of gyrA and gyrB genes
Methicillin-resistant Acquisition of staphylococcal cassette chromosome (Harkins et al., 2017; Zaher
Staphylococcus mec (SSCmec) containing a methicillin resistance gene Fusarium tricinctum Corda. Hordeum sativum Jess. et al., 2015; Vu et al., 2019;
aureus (mecA) by conjugation Streptomyces cavourensis Cinnamomum cassia Ibrahim et al., 2015)
Nigrospora sphaerica Presl.
Swietenia macrophylla
King
Vancomycin-resistant Presence of vanA and/or vanB type vancomycin Streptomyces NRRL 3052 Kennedia nigriscans (Christina et al., 2013;
Enterococcus faecalis resistance operon Rushton-Green et al., 2019)
MDR Escherichia coli Acquisition of blaCTX-M, blaNDM, blaOXA-48, presence of Penicillium sp. Curcuma longa (Dunn et al., 2019; Singh
mobile colistin resistance gene mcr et al., 2014)
Methicillin-resistant Presence of lnuA gene encoding for lincosamide Streptomyces cavourensis Cinnamomum cassia (Lozano et al., 2012; Vu et al.,
Staphylococcus resistance, vga gene encoding ABC transporters leading Presl. 2019)
epidermidis to streptogramin A resistance
MDR Klebsiella Presence of virulence gene rpmA2 and the Colletotrichum sp. Aegiceras corniculatum (Bin et al., 2014; Dong et al.,
pneumoniae carbapenemase gene bla KPC-2 on a ~240 kb plasmid, Grignardia sp Aegiceras corniculatum 2018; Mancini et al., 2018;
upregulation of pmrH operon, mutation in mgrB, crrAB Wright et al., 2015)
and phoQ genes, production of OXA- 232, ESBL CTX-M-
15 and 16s rRNA methyltransferase RmtF

Since microbes are ubiquitous in tissues of medicinal plants, they can
prove to be an excellent source of therapeutic agents because of their
abundance, ability to produce metabolites similar to those of the me­
dicinal plant on which they are present, and easy extraction of these
compounds for pharmaceutical use. They can be cultured on media even
when the conditions are hostile for the plant to grow, making them
better candidates for discovery of novel drugs.
7.1.1. Fungal endophytes
Fungi are the largest producers of secondary metabolites as
compared to any other endophyte owing to a higher frequency of
isolation resulting in greater chances of discovering an antimicrobial
compound from different species (Radić and Štrukelj, 2012). An endo­
phytic fungus, Colletotrichum gloeosporioides is a potent source for pro­
duction of phenolic compounds and flavonoids (Zargar et al., 2011). It is
present on an aromatic medicinal shrub Vitex negundo L. which has been
used for curing rheumatism, chronic bronchitis, cold and is widely used
in Chinese herbal medicine (Desale and Bodhankar, 2013). The fungal
extract has shown significant toxicity against organisms like Staphylo­
coccus aureus MTCC 3160, Bacillus subtilis MTCC 619, Pseudomonas
aeruginosa MTCC 2488, Escherichia coli MTCC 4296, and Candida albi­
cans MTCC 3018 (Arivudainambi et al., 2011). The extract has also
shown synergistic effects with antibiotics like methicillin, penicillin, and
vancomycin in case of MDR Staphylococcus aureus by significantly
decreasing the MIC values. Thereby, it can be inferred that the fungal
metabolite may somehow restore the activity of beta-lactam rings of
antibiotics like methicillin and penicillin which are initially degraded by
the acquisition of resistance against these drugs by chemically modi­
fying the structure or the target of these antibiotics or rendering the
peptidoglycan binding enzyme ineffective. C. gloeosporioides extract
isolated from medicinal plant Phlogacanthus thyrsiflorus Nees has
demonstrated high biocontrol activity towards Staphylococcus aureus
ATCC 25923 and Pseudomonas aeruginosa ATCC 27853 (Devi and Singh,
2013). The plant Ficus carica L. which has been used as a remedy for
various ailments of the gastrointestinal, respiratory, and cardiovascular
systems harbours the endophyte Apergillus tamarii. The endophytic
fungus produces a new cyclic pentapeptide called malformin E which
has displayed noteworthy cytotoxicity towards Bacillus subtilis, Staphy­
lococcus aureus, Pseudomonas aeruginosa, and Escherichia coli with MIC
values <1, whereas for fungi like Penicillium chrysogenum, Candida
albicans, and Fusarium solani, the MIC values were relatively higher (Ma
et al., 2016). Yet another useful endophyte Muscodor tigerii inhabiting
the stem of plant Cinnamomum camphora (L.) J.Presl found in Darjeeling,
India is the source of many volatile organic compounds (VOCs) like
4-Octadecylmorpholine, 1-Tetradecanamine, N, N-dimethyl, 1,2-Benze­
nedicarboxylic acid, mono (2-ethylhexyl) ester, squalene, and phytol.
The VOCs possess antibacterial and antifungal activity and have dis­
played lethality against two organisms Alternaria alternata and Cerco­
spora beticola whereas the growth of pathogens such as Rhizoctonia
solani, Penicillium marneffei, and Aspergillus flavus was suppressed by
72%, 42%, and 40.2% respectively. For Staphylococcus aureus, the in­
hibition rate was 81% while for Candida albicans and Pseudomonas aer­
uginosa the rates stood between 50–63% (Saxena et al., 2015). The fruit
of Hordeum sativum var. celeste (L.) Vilm., a folk medicine for dysentery
anchors a novel enniatin antibiotic producing fungus Fusarium tricinctum
Corda. In addition to the four already known enniatins (A, A1, A2, and
B1), EN Q has been reported as the new analogue of EN A and EN B2 has
been discovered for the first time. The six ENs have shown mild anti
leishmanial and antibacterial activity against Leishmania donovani ATTC
39930D and methicillin-resistant Staphylococcus aureus, respectively.
These antibiotics inhibit microbial growth by interfering with the ion
selectivity of the cell wall by forming complexes with cations or by
hampering the activity of the acyl-CoA:cholesterol acyltransferase
enzyme. They are also known to form complexes with cations facili­
tating their transport through cell membranes. Surprisingly, the extract
from F. tricintum exhibited high antagonistic action against Plasmodium
falciparum by inhibiting the enzyme P. falciparum thioredoxin reductase
(PfTrxR) (Zaher et al., 2015). Further, the fungus Nigrospora sphaerica
CL-OP 30 colonizing the ethnobotanical plant Swietenia macrophylla
King has shown profound biocontrol activities against
methicillin-resistant Staphylococcus aureus and Klebsiella pneumoniae.
The time dependent inhibition of cells occurs by pore formation and cell
debris accumulation due to cell wall and cell membrane rupture in
MRSA, while in K. pneumoniae the cell morphology was disrupted and
leakage of the cellular components was observed, indicating substantial
damage to either the peptidoglycan layer or plasma membrane or both.
In addition, the thickening of periplasm suggested rapid influx of water
into the cell after cell wall damage subsequently causing cell lysis
(Ibrahim et al., 2015). A medicinal shrub, Aegiceras corniculatum (L.)
Blanco used for treating ailments like arthritis, bacterial infections, and

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Table 2
Various endophytes, their sources and the microorganisms against which bioactivity has been reported.
Endophyte Plant(S) From Secondary Metabolites Test Microbes And The Level Of Inhibition References
Which It Is
Extracted

Fungal endophytes
Colletotrichum Vitex negundo L., Phenolic compounds and flavonoids High: Staphylococcus aureus, Pseudomonas (Desale and Bodhankar,
gloeosporioides Phlogacanthus aeruginosa 2013,Zargar et al., 2011,
thyrsiflorus Nees Moderate: Bacillus subtilis, Pseudomonas Arivudainambi et al., 2011)
aeruginosa, Escherichia coli, Candida albicans

Apergillus tamarii Ficus carica Malformin E High: Bacillus subtilis, Staphylococcus aureus, (Ma et al., 2016)
Pseudomonas aeruginosa, Escherichia coli
Moderate: Penicillium chrysogenum
Pseudomonas aeruginosa
Low: Candida albicans, Fusarium solani

Fusarium tricinctum Hordeum sativum Enniatins A, A1, A2, B1, EN Q High: Plasmodium falciparum (Zaher et al., 2015)
Corda var. celeste (L.) Vilm Moderate: Leishmania donovani, \methicillin-
resistant Staphylococcus aureus
Nigrospora sphaerica Bruguiera arnottiana Nigronapthaphenyl High: Bacillus subtilis TISTR 088 and Bacillus (Ukwatta et al., 2019)
Wight ex Arn. cereus TISTR 688

Khuskia oryzae Bidens bipinnata L. 9-oxo-(10E, 12E)- octadecadienoic acid, 8- High: Bacillus subtilis (Abdou and Shaker, 2013)
oxo-(9E, 11E)-octadecadienoic acid

Fusarium tricinctum Rhododendron Trtesin Moderate: Staphylococcus carnosus, Candida (Tejesvi et al., 2013)
tomentosum Harmaja albicans, Candida utilis
Aspergillus nidulans, Ocimum basilicum L 9-octadecenoic acid, methyl ester methyl High to moderate: Staphylococcus aureus ATCC (Sharaf et al., 2021)
Aspergillus fumigatus stearate, 9,12-octadecadienoic acid, 2-hy­ 6538, Bacillus cereus ATCC 10,987, Bacillus
and Aspergillus flavus droxy-1-(hydroxymethyl) ethyl ester and 9,17- subtilis ATCC 6633, Escherichia coli ATCC 8739,
octadecadienal Salmonella typhimurium ATCC14028, Klebsiella
pneumonia ATCC 13,883, Pseudomonas
aeruginosa ATCC 9072 and Candida albicans
ATCC10231
Chloridium sp Azadirachta indica A. Javanicin High: Pseudomonas sp (Nisa et al., 2015)
Juss.
Bacterial Endophytes
Streptomyces Cinnamomum cassia 1- monolinolein, bafilomycin D, nonactic acid, High: methicillin resistant Staphylococcus (Vu et al., 2019)
cavourensis YBQ59 (L.) J.Presl daidzein, 3’- hydroxydaidzein, 5,11-epoxy-10- aureus ATCC 33591, methicillin resistant
cadinanol Staphylococcus epidermidis ATCC 35984
Streptomyces sp BT01 Boesenbergia rotunda Fisetin, Naringenin, 3’-hydrixydaidzein and Moderate: Bacillus cereus and Bacillus subtilis (Abdelwahab et al., 2011;
(L.) Xenognosin B, 7-merthoxy-3, 3’,4’,6- Low: Escherchia coli and Pseudomonas Taechowisan et al., 2014)
tetrahydroxyflavone and 2’,7- dihydroxy- 4’, aeruginosa.
5’- dimethoxyisoflavone.
Bacillus mojavensis* Bacopa monnieri (L.) Lipopeptide BmB 4 consisting of surfactin and Escherchia coli, Staphylococcus aureus, Klebsiella (Jasim et al., 2016)
Wettst fengycin pneumoniae and Salmonella typhi

High: Zone of inhibition ≥ 15 mm or MIC ≤ 10 ug/mL

Moderate: Zone of inhibition: > 7 mm to < 15 mm or MIC: >10 μg/mL to < 25 μg/mL
Low: Zone of inhibition < 7 mm or MIC > 25 μg/mL
*
Level of activity not mentioned in the literature.

inflammation, is a reservoir of biologically important endophytes out of
which three have shown exceptional microbicidal properties. Colleto­
trichum sp. isolated from the shrub has inhibited the growth of MDR
Klebsiella pneumoniae, Acinetobacter baumannii, Bacillus cereus, and
Escherichia coli whereas Grignardia sp. has exhibited remarkable activity
against MDR K. pneumoniae and B.cereus. Cladosporium sp. isolated from
the same shrub is an effective biocontrol agent against B.cereus and E.coli
(Bin et al., 2014). Similarly, the Brazilian folk medicine plant Bauhinia
forficatea Link has proven to be a treasure house of useful endophytes
including Khuskia oryzae with exceptional antimicrobial properties
against Salmonella typhi while Penicillium glabrum is highly efficient in
killing Streptococcus pyogenes, Staphylococcus aureus, Mycobacterium
smegmatis, and Bacillus subtilis. Two other endophytes Penicillium
commune and Gibberella baccata have exhibited noteworthy activities
against Staphylococcus aureus, Streptococcus pyogenes, Bacillus subtilis,
and Enterococcus faecalis (Bezerra et al., 2015). Trtesin, a fungal defensin
produced by the endophytic fungus Fusarium tricinctum isolated from
Rhododendron tomentosum Harmaja, a medicinal shrub found across the
northern hemisphere, has demonstrated mild antimicrobial property
against human pathogens like Staphylococcus carnosus, Candida albicans,
and Candida utilis as well as the plant pathogen Fusarium oxysporum
(Tejesvi et al., 2013). Endophytic fungal strains like Aspergillus nidulans,
Aspergillus fumigatus, and Aspergillus flavus have been isolated from the
medicinal plant Ocimum basilicum L. They are known to produce various
compounds including 9-octadecenoic acid, methyl ester methyl stearate,
9,12-octadecadienoic acid, 2-hydroxy-1-(hydroxymethyl) ethyl ester,
and 9,17-octadecadienal, exhibiting significant bioactivity against
Staphylococcus aureus ATCC 6538, Bacillus cereus ATCC 10,987, Bacillus
subtilis ATCC 6633, Escherichia coli ATCC 8739, Salmonella typhimurium
ATCC14028, Klebsiella pneumonia ATCC 13,883, Pseudomonas aeruginosa
ATCC 9072, and Candida albicans ATCC10231 (Sharaf et al., 2021).
Chloridium sp. present on neem has been reported to produce a potent
antibacterial naphthaquinone named Javanicin displaying high activity
against Pseudomonas sp. (Nisa et al., 2015).
7.1.2. Bacterial endophytes
Nanoparticles synthesised from Streptomyces coelicolor strain E72
extract from the medicinal plant Ocimum sanctum L. have exhibited
remarkable antimicrobial activity against Shigella flexneri followed by
Staphylococcus aureus, Streptococcus pneumonia, and Klebsiella pneumonia.
Moderate antibacterial activity was observed against Escherichia coli,
Proteus vulgaris, Salmonella typhimurium, and Bacillus cereus

6
P. Pasrija et al.
(El-Moslamy, 2018). It has been reported that these nanoparticles attack
the bacterial cell wall and lead to the destabilisation of cells thereby
causing lysis. Nanoparticles like those synthesised from Streptomyces
coelicolor E72, have been made using the Penicillium sp. isolated from the
leaves of therapeutic plant Curcuma longa L. These nanoparticles have
demonstrated high germicidal action against MDR Escherichia coli and
Staphylococcus aureus (Singh et al., 2014). Another important remedial
plant Cinnamomum cassia (L.) J.Presl anchors the endophyte Strepto­
myces cavourensis YBQ59 which is known to be a producer of a potent
antimicrobial compound (at an optimum temperature of 30 ◦ C) highly
efficient against methicillin-resistant Staphylococcus aureus ATCC 3359,
methicillin-resistant Staphylococcus epidermidis ATCC 35984 (MRSE),
and Salmonella typhimurium ATCC 14028 as compared to the conven­
tional antibiotic, azithromycin (Vu et al., 2019). Litsea cubeba (Lour.)
Pers., a Chinese medicinal herb used for treating headache, sore and
furuncles, depression etc. is a reservoir of the bioactive endophyte
Streptomyces griseorubens MPT42. The endophytic extract in combination
with the essential oil obtained from the plant showed synergistic activity
against Bacillus cereus, Bacillus subtilis, Staphylococcus aureus, MRSE,
Listeria innocua, Aeromonas hydrophila, Escherichia coli, and Pseudomonas
aeruginosa (Nguyen et al., 2019). The endophytic strain Streptomyces sp
BT01 isolated from the root tissue of a medicinal herb, Boesenbergia
rotunda (L.) used for treating peptic ulcers, has been reported to be a
storehouse of secondary metabolites (Abdelwahab et al., 2011; Tae­
chowisan et al., 2014). Apart from the previously known flavonoids i.e.,
fisetin, naringenin, 3’-hydrixydaidzein, and xenognosin B, the bacterial
strain produces two new flavonoids, 7-merthoxy-3, 3’,4’,6- tetrahy­
droxyflavone and 2’,7- dihydroxy- 4’, 5’-dimethoxyisoflavone. The
extract has shown considerable activity against Bacillus cereus and Ba­
cillus subtilis, along with weak antagonist activity against Escherchia coli
and Pseudomonas aeruginosa. Another important endophyte Bacillus
mojavensis has been extracted from the plant Bacopa monnieri (L.) Wettst
known for its role in improving intelligence and memory with potential
to be used for treating Alzheimer’s disease (Uabundit et al., 2010). The
endophyte produces a lipopeptide BmB 4 consisting of surfactin and
fengycin, showing significant activity against Escherchia coli, Staphylo­
coccus aureus, Klebsiella pneumoniae, and Salmonella typhi (Jasim et al.,
2016). Lipopeptide compounds have been reported to interfere with the
microbial cytoplasmic membrane permeability by creating pores within
the lipid bilayer, thereby causing the leakage of K+ ions. Figure 1.
summarizes the bacterial and fungal endophytes and their metabolites
and Table 1 provides a detailed analyses of source and activity of fungal
and bacterial endophytes.
7.2. Mechanism of action
Endophytic compounds have proven to be quite effective against
various bacterial and fungal strains which cause diseases in humans.
However, the exact mechanism of this biocontrol activity has not been
accurately elucidated. Numerous in vitro studies have been performed
on various pathogenic microbes and the Scanning Electron Microscopy
(SEM) micrographs obtained from these studies have shed some light on
the possible mechanism of action. In a study carried out by Yenn et al.,
extracts from an endophytic fungus Penicillium purpurogenum ED76 iso­
lated from Swietenia macrophylla King showed high bioactivity against
pathogens like Staphylococcus aureus, Acintobacter anitratus, and Candida
albicans (Yenn et al., 2017). The SEM micrographs of Staphylococcus
aureus upon treatment with the sterol containing extract showed sig­
nificant distortion of the cocci shape with invaginated cell walls and
leakage of cellular components. A similar study was performed using the
extracts of Alternaria alternata AE1 isolated from the medicinal tree
Azadirachta indica A.Juss. (Chatterjee et al., 2019). The micrographs of
the treated bacteria revealed severe damage to the cell morphology
leading to release of DNA and proteins from the bacterial cells. The
consistency in the results suggests that the bioactive metabolites
extracted from endophytes disrupt the cell wall biosynthesis as well as
7
Phytomedicine Plus 2 (2022) 100249
the cell membrane permeability leading to cell lysis and discharge of the
intracellular constituents (Fig. 2). The damaged cells also lose their
metabolic activities and become irreparable (Taufiq and Darah, 2019).
Studies have also revealed that endophytic metabolites contain signifi­
cant catalase inhibiting properties, reducing the resistance of pathogen
towards oxidative stress and attack by macrophages (Mbekou et al.,
2021). Endophytic extracts have also displayed noteworthy activities
against HIV by either acting as protease inhibitors or interfering with the
HIV envelope protein and chemokine co-receptor interaction, thus
indicating the possible mode of action by which these extracts can help
fight-off infections (Vora et al., 2021; Banyal et al., 2021).
7.3. Toxicity and side effects of endophytic compounds
Endophytes have been deemed as safer alternatives for treating
pathogenic attacks as they have little or no side effects. An in-vivo study
for treating Plasmodium berghei PZZ1/100 infected mice with an endo­
phytic compound gancidin W extracted from Streptomyces SUK10 has
highlighted the harmless nature of such compounds (Zin et al., 2017).
ICR strain mice treated with GW (acute treatment: 7 days, subacute
treatment: 28 days) were divided into two groups based on the exposure
to the parasite: a) without infection and b) immediately 2 h after
infection on day zero. Stained histological sections of the spleen, kidney
and liver tissues from the GW treated mice and the control group did not
show any toxicity characteristics like vacuolization of cytoplasm or
vascular shrinkage. The results were consistent with the biochemical
tests performed on the blood samples taken from the organs indicating
that endophytes are quite effective and do not show any undesirable
effects on the treated host. In another experiment on Caenorhabditis
elegans infected with S. aureus, nanoparticles synthesized using the
fungal extract from Lasiodiplodia pseudotheobromae isolated from Eupa­
torium triplinerve Vahl have decreased the mortality rate in the infected
C. elegans and was nontoxic to the nematode (Ranjani et al., 2020). This
observation is in stark contrast to the earlier studies performed using
only silver nanoparticles which were observed to be toxic and lethal to
C. elegans.
7.4. Other fields where Endophytes have been exploited
Endophytes have been the subject of experimentation to explore
their products as biocontrol agents. Bacterial and fungal endophytes
isolated from the medicinal plant Teucrium polium L. have shown
exceptional plant growth promoting properties by production of
phytohormone indole acetic acid (IAA), phosphorus mobilization, syn­
thesis of ammonia and degrading enzymes which protect the plant from
invasion by microorganisms (Hassan, 2017). In another study, a positive
correlation has been found between the accumulation of alkaloids and
the abundance of fungal endophytes in the plant Lycoris radiata (L’Hèr.)
Herb. (Zhou et al., 2020).Various antiviral compounds have also been
isolated from fungal endophytes. Endophytic fungus Cytonaema sp. has
been known to produce two compounds-cytonic acid A and B which
inhibit human cytomegalovirus (hCMV) protease (Jalgaonwala et al.,
2011). Endophytes have also been known to possess insecticidal prop­
erties with the first nodulisporic agent to be isolated from endophytes:
Nodulispotium sp and Bontia Daphnoides. They can be potentially used in
the agrochemical sector as cryptocin, a tetramic acid extracted from the
endophytic fungus Cryptosporiopsis quercina isolated from Tripterygium
wilfordii Hook. f. has shown compelling activity against the plant pests
Pyricularia oryzae (Nisa et al., 2015). Various in-vivo studies involving
extracts from endophytes have been carried out to assess their bioactive
properties. An endophyte Schizophyllum commune Fr. isolated from Aloe
vera (L.) Burm.f. has been tested on streptozotocin induced diabetic mice
for its antidiabetic properties (Sharma et al., 2021). The fungal extract
was found out to be rich in phenols and terpenoids. The treated mice not
only displayed a decrease in the blood sugar level but also had reduced
levels of creatinine, BUN, potassium and FeNa as compared to the
P. Pasrija et al.
untreated mice. Another study for assessing the antiarthritic activity of
endophytic fungi isolated from Elaeocarpus floribundus Blume was per­
formed on albino mice with complete Freund’s adjuvant induced poly­
arthritis (Mazumder et al., 2021). The fungi isolated included Aspergillus
niger and Rhizopus oryzae which suppressed paw edema as well as
decreased the paw volume in the test group even after 12 days of
infection. However, similar studies for assessing the antimicrobial po­
tential of endophytes have still not been carried out.
8. Conclusion and future perspectives
At the current rate of growth, multidrug resistance has become a
serious problem with the potential of turning into a global pandemic
claiming numerous lives. Therefore, it has become crucial to find
effective solutions not only for reducing drug resistance but its complete
eradication. Despite the utilisation of ethnomedicinal plants for treating
various ailments, their limited availability is a major downfall. This is
where endophytes can come into play; their abundance as well as ability
to produce effectual antimicrobial compounds can be exploited for
pharmaceutical applications. Endophytes have been reported to harbour
several beneficial features such as anti-inflammatory, anti-cancerous,
anti-microbial, and insecticidal and pesticidal properties; they also
decrease phytotoxicity and improve phytoremediation. In this review,
we focused on the antimicrobial properties of endophytes mainly against
MDR organisms and enlisted several potent fungal and bacterial endo­
phytes. The Phylum Ascomycota and Actinobacteria represent the two
major classes of endophytes that are responsible for the production of
antibiotics. The major bacterial endophyte include Streptomyces sp.,
which are responsible for maximum antimicrobial activity reported. The
major players responsible for conferring the anti-microbial potential to
endophytes are secondary metabolites such as flavonoids, alkaloids,
saponins, terpenoids, phenolics, and lipids. The extracts from endo­
phytes have been reported to harbour anti-microbial properties against
several drug-resistant microorganisms such as MRSA, MRSE, Bacillus sp.,
and Shigella flexneri. Thus, this review evaluates and establishes endo­
phytes as potent source of therapeutic compounds, which will be
beneficial for replacing imprudent use of antibiotics.
Although the antimicrobial properties of various endophytic micro­
organisms have already been elucidated, the reviewed literature search
could not answer the following questions:
• Which are the pharmacophores of anti-microbial endophyte
extracts?
• Specific receptors on host cell wall with which the endophyte me­
tabolites interact rupturing the cell wall?
• What is the exact mechanism of action of the antimicrobial com­
pounds derived by endophytes?
• Can the secondary metabolites be explored as potential vaccine
candidates?
These are the aspects which need to be taken-up in future research to
establish metabolites secreted from endophytes as potential therapeutic
compounds. Elucidating the exact mechanism of action, pharmaco­
phores, and cell wall receptors will aid in modifying the secondary
metabolites for developing better drug candidates.
9. Author Contributions
All data were generated in-house, and no paper mill was used. All
authors agree to be accountable for all aspects of work ensuring integrity
and accuracy.
Anju Katyal: Conceptualization, Writing-reviewing and editing;
Purvashi Pasrija: Data curation, writing-original draft preparation;
Meetali Girdhar: Conceptualization, Writing-original draft, reviewing
and editing; Mukesh Kumar: Writing-reviewing and editing; Creating
Figures; Shivani Arora: Writing-reviewing and editing
8
Phytomedicine Plus 2 (2022) 100249
Declaration of Competing Interest
Authors wish to confirm that there are no known conflicts of interest
associated with this publication and there has been no significant
financial support for this work that could have influenced its outcome
References
Abdelwahab, S.I., Mohan, S., Abdulla, M.A., Sukari, M.A., Abdul, A.B., Taha, M.M.E.,
Syam, S., Ahmad, S., Lee, K.H., 2011. The methanolic extract of Boesenbergia
rotunda (L.) Mansf. and its major compound pinostrobin induces anti-ulcerogenic
property in vivo: possible involvement of indirect antioxidant action. Journal of
ethnopharmacology 137 (2), 963–970, 10.1016/j.jep.2011.07.010.
Abdou, R., Shaker, K., 2013. Bioactive metabolites of the endophyte Khuskia oryzae
isolated from the medicinal plant bidens bipinnata. Asian Journal of Pharmacy and
Life Science ISSN 4423, 2231.
Adnan, M., Alshammari, E., Ashraf, S.A., Patel, K., Lad, K., Patel, M., 2018. Physiological
and molecular characterization of biosurfactant producing endophytic fungi Xylaria
regalis from the cones of Thuja plicata as a potent plant growth promoter with its
potential application. BioMed research international. https://doi.org/10.1155/
2018/7362148, 2018.
Andersson, D.I., Hughes, D., 2010. Antibiotic resistance and its cost: is it possible to
reverse resistance? Nature Reviews Microbiology 8 (4), 260–271. https://doi.org/
10.1038/nrmicro2319.
Arivudainambi, U.E., Anand, T.D., Shanmugaiah, V., Karunakaran, C., Rajendran, A.,
2011. Novel bioactive metabolites producing endophytic fungus Colletotrichum
gloeosporioides against multidrug-resistant Staphylococcus aureus. FEMS
Immunology & Medical Microbiology 61 (3), 340–345, 10.1111/j.1574-
695X.2011.00780.x.
Augustin, JM, Kuzina, V, Andersen, SB, Bak, S., 2011. Molecular activities, biosynthesis
and evolution of triterpenoid saponins. Phytochemistry 72 (6), 435–457. https://doi.
org/10.1016/j.phytochem.2011.01.015. Apr 1.
Banyal, A., Thakur, V., Thakur, R., Kumar, P., 2021. Endophytic microbial diversity: a
new hope for the production of novel anti-tumor and anti-HIV agents as future
therapeutics. Current Microbiology 78 (5), 1699–1717. https://doi.org/10.1007/
s00284-021-02359-2.
Bezerra, J.D., Nascimento, C.C., Barbosa, R.D.N., da Silva, D.C., Svedese, V.M., Silva-
Nogueira, E.B., Gomes, B.S., Paiva, L.M., Souza-Motta, C.M., 2015. Endophytic fungi
from medicinal plant Bauhinia forficata: Diversity and biotechnological potential.
Brazilian Journal of Microbiology 46, 49–57. https://doi.org/10.1590/S1517-
838246120130657.
Bin, G., Yanping, C., Hong, Z., Zheng, X., Yanqiu, Z., Huaiyi, F., Qiupin, Z., Chenxiao, Z.,
2014. Isolation, characterization and anti-multiple drug resistant (MDR) bacterial
activity of endophytic fungi isolated from the mangrove plant, Aegiceras
corniculatum. Tropical Journal of Pharmaceutical Research 13 (4), 593–599,
10.4314/tjpr.v13i4.16.
Blair, J.M., Webber, M.A., Baylay, A.J., Ogbolu, D.O., Piddock, L.J., 2015. Molecular
mechanisms of antibiotic resistance. Nature reviews microbiology 13 (1), 42–51.
https://doi.org/10.1038/nrmicro3380.
Bollinger, H., Kathariou, S., 2017. The current state of macrolides resistance in
Campylobacter spp. : Trends and impacts of resistance mechanism. Appl Environ
Microbiol 83. https://doi.org/10.1128/AEM.00416-17 e00416-e7.
Centers for Disease Control and Prevention, 2019. Antibiotic resistance threats in the
United States, 2019. US Department of Health and Human Services, Centres for
Disease Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats
-report/2019-ar-threats-report-508.pdf (accessed 21 November, 2020).
Chandra, H, Bishnoi, P, Yadav, A, Patni, B, Mishra, AP, Nautiyal, AR., 2017.
Antimicrobial resistance and the alternative resources with special emphasis on
plant-based antimicrobials—a review. Plants 6 (2), 16. Jun10.3390/plants6020016.
Chatterjee, S., Ghosh, R., Mandal, N.C., 2019. Production of bioactive compounds with
bactericidal and antioxidant potential by endophytic fungus Alternaria alternata AE1
isolated from Azadirachta indica A. Juss. PLoS One 14 (4). p.e0214744. 10.1371/
journal.pone.0214744.
Christina, A., Christapher, V., Bhore, S.J., 2013. Endophytic bacteria as a source of novel
antibiotics: an overview. Pharmacognosy reviews 7 (13), 11. https://doi.org/
10.4103/0973-7847.112833.
Cohen, N.R., Lobritz, M.A., Collins, J.J., 2013. Microbial persistence and the road to drug
resistance. Cell host & microbe 13 (6), 632–642. https://doi.org/10.1016/j.
chom.2013.05.009.
Comas, I., Borrell, S., Roetzer, A., et al., 2012. Whole-genome sequencing of rifampicin-
resistant Mycobacterium tuberculosis strains identifies compensatory mutations in
RNA polymerase genes. Nat Genet 44, 106–110. https://doi.org/10.1038/ng.1038.
Cushnie TT, Cushnie B, Lamb AJ. Alkaloids: An overview of their antibacterial,
antibiotic-enhancing and antivirulence activities. International journal of
antimicrobial agents. 2014 Nov 1;44(5):377-86. 10.1016/j.ijantimicag.2014.06.001.
Cheynier, V, Comte, G, Davies, KM, Lattanzio, V, Martens, S., 2013. Plant phenolics:
recent advances on their biosynthesis, genetics, and ecophysiology. Plant physiology
and biochemistry 72, 1–20. Nov 110.1016/j.plaphy.2013.05.009.
da Silva, P.E.A., Von Groll, A., Martin, A., Palomino, J.C., 2011. Efflux as a mechanism
for drug resistance in Mycobacterium tuberculosis. FEMS Immunology & Medical
Microbiology 63 (1), 1–9. https://doi.org/10.1111/j.1574-695X.2011.00831.x.
Dai, J, Mumper, RJ., 2010. Plant phenolics: extraction, analysis and their antioxidant and
anticancer properties. Molecules 15 (10), 7313–7352. https://doi.org/10.3390/
molecules15107313. Oct.
P. Pasrija et al.
Davies, J., Davies, D., 2010. Resistance origins and evolution of antibiotic. Microbiology
and Molecular Biology reviews. Microbiol Mol Biol Rev 74 (3), 417–433. https://doi.
org/10.1128/MMBR.00016-10.
Desale, M.G., Bodhankar, M.G., 2013. Antimicrobial activity of endophytic fungi isolated
from Vitex negundo Linn. Int J Curr Microbiol App Sci 2 (12), 389–395.
Devi, N.N., Singh, M.S., 2013. GC-MS Analysis of metabolites from endophytic fungus
Colletotrichum gloeosporioides isolated from Phlogacanthus thyrsiflorus Nees. Int J
Pharm Sci 23 (2), 392–395. https://doi.org/10.1063/1.5061895.
El-Deeb, B., Fayez, K., Gherbawy, Y., 2013. Isolation and characterization of endophytic
bacteria from Plectranthus tenuiflorus medicinal plant in Saudi Arabia desert and
their antimicrobial activities. Journal of plant interactions 8 (1), 56–64. https://doi.
org/10.1080/17429145.2012.680077.
El-Moslamy, S.H., 2018. Bioprocessing strategies for cost-effective large-scale biogenic
synthesis of nano-MgO from endophytic Streptomyces coelicolor strain E72 as an
anti-multidrug-resistant pathogens agent. Scientific reports 8 (1), 1–22. 10.1038/s41
598-018-22134-x.
Dong, N., Lin, D., Zhang, R., Chan, E.W.C., Chen, S., 2018. Carriage of bla KPC-2 by a
virulence plasmid in hypervirulent Klebsiella pneumoniae. Journal of Antimicrobial
Chemotherapy 73 (12), 3317–3321. https://doi.org/10.1093/jac/dky358.
Dunn, S.J., Connor, C., McNally, A., 2019. The evolution and transmission of multi-drug
resistant Escherichia coli and Klebsiella pneumoniae: the complexity of clones and
plasmids. Current opinion in microbiology 51, 51–56. https://doi.org/10.1016/j.
mib.2019.06.004.
Egamberdieva, D., Wirth, S., Behrendt, U., Ahmad, P., Berg, G., 2017. Antimicrobial
activity of medicinal plants correlates with the proportion of antagonistic
endophytes. Frontiers in microbiology 8, 199. https://doi.org/10.3389/
fmicb.2017.00199.
Faizal, A., Geelen, D., 2013. Saponins and their role in biological processes in plants.
Phytochemistry reviews 12 (4), 877–893. https://doi.org/10.1007/s11101-013-
9322-4.
Fodor, A., Abate, B.A., Deák, P., Fodor, L., Gyenge, E., Klein, M.G., Koncz, Z., Muvevi, J.,
Ötvös, L., Székely, G., Vozik, D., 2020. Multidrug Resistance (MDR) and collateral
sensitivity in bacteria, with special attention to genetic and evolutionary aspects and
to the perspectives of antimicrobial peptides—A review. Pathogens 9 (7), 522,
10.3390/pathogens9070522.
Ghasemzadeh, A, Ghasemzadeh, N., 2011. Flavonoids and phenolic acids: Role and
biochemical activity in plants and human. Journal of medicinal plants research 5
(31), 6697–6703. Dec 1610.5897/JMPR11.1404.
Giedraitienė, A., Vitkauskienė, A., Naginienė, R., Pavilonis, A., 2011. Antibiotic
resistance mechanisms of clinically important bacteria. Medicina 47 (3), 19,
10.3390/medicina47030019.
Harkins, C.P., Pichon, B., Doumith, M., Parkhill, J., Westh, H., Tomasz, A., de
Lencastre, H., Bentley, S.D., Kearns, A.M., Holden, M.T., 2017. Methicillin-resistant
Staphylococcus aureus emerged long before the introduction of methicillin into
clinical practice. Genome biology 18 (1), 1–11. https://doi.org/10.1186/s13059-
017-1252-9.
Hassan, S.E.D., 2017. Plant growth-promoting activities for bacterial and fungal
endophytes isolated from medicinal plant of Teucrium polium L. Journal of
advanced research 8 (6), 687–695. https://doi.org/10.1016/j.jare.2017.09.001.
Hughes, D., Andersson, D.I., 2015. Evolutionary consequences of drug resistance: shared
principles across diverse targets and organisms. Nature Reviews Genetics 16 (8),
459–471. https://doi.org/10.1038/nrg3922.
Ibrahim, D., Lee, C.C., Yenn, T.W., Zakaria, L., Sheh-Hong, L., 2015. Effect of the extract
of endophytic fungus, Nigrospora sphaerica CL-OP 30, against the growth of
methicillin-resistant Staphylococcus aureus (MRSA) and Klebsiella pneumonia cells.
Tropical Journal of Pharmaceutical Research 14 (11), 2091–2097. https://doi.org/
10.4314/tjpr.v14i11.20.
Imenshahidi, M., Hosseinzadeh, H., 2016. Berberis vulgaris and berberine: an update
review. Phytotherapy research 30 (11), 1745–1764. https://doi.org/10.1002/
ptr.5693.
Jalgaonwala, R.E., Mohite, B.V., Mahajan, R.T., 2011. A review: natural products from
plant associated endophytic fungi. J Microbiol Biotechnol Res 1 (2), 21–32 http://
scholarsresearchlibrary.com/.
Jamuna, S., Paulsamy, S., Karthika, K., 2013. In vitro antibacterial activity of leaf and
root extracts of Hypochaeris radicata L.(Asteraceae)–a medicinal plant species
inhabiting the high hills of Nilgiris, the Western Ghats. International Journal of
Pharmacy and Pharmaceutical Sciences 5 (1), 175–178. https://doi.org/10.26524/
krj11.
Jasim, B., Sreelakshmi, S., Mathew, J., Radhakrishnan, E.K., 2016. Identification of
endophytic Bacillus mojavensis with highly specialized broad spectrum antibacterial
activity. 3. Biotech 6 (2), 1–10. https://doi.org/10.1007/s13205-016-0508-5.
Kabera, J.N., Semana, E., Mussa, A.R., He, X., 2014. Plant secondary metabolites:
biosynthesis, classification, function and pharmacological properties. J Pharm
Pharmacol 2 (7), 377–392.
Kaul, S., Gupta, S., Ahmed, M., Dhar, M.K., 2012. Endophytic fungi from medicinal
plants: a treasure hunt for bioactive metabolites. Phytochemistry reviews 11 (4),
487–505. https://doi.org/10.1007/s11101-012-9260-6.
Kester, J.C., Fortune, S.M., 2014. Persisters and beyond: mechanisms of phenotypic drug
resistance and drug tolerance in bacteria. Critical reviews in biochemistry and
molecular biology 49 (2), 91–101. https://doi.org/10.3109/
10409238.2013.869543.
Kumar, S., Aharwal, R.P., Shukla, H., Rajak, R.C., Sandhu, S.S., 2014. Endophytic fungi:
as a source of antimicrobials bioactive compounds. World J Pharm Sci 3 (2),
1179–1197.
Kusari, S., Verma, V.C., Lamshoeft, M., Spiteller, M., 2012. An endophytic fungus from
Azadirachta indica A. Juss. that produces azadirachtin. World Journal of
9
Phytomedicine Plus 2 (2022) 100249
Microbiology and Biotechnology 28 (3), 1287–1294. https://doi.org/10.1007/
s11274-011-0876-2.
Laxminarayan, R., Duse, A., Wattal, C., Zaidi, A.K., Wertheim, H.F., Sumpradit, N.,
Vlieghe, E., Hara, G.L., Gould, I.M., Goossens, H., Greko, C., 2013. Antibiotic
resistance—the need for global solutions. The Lancet infectious diseases 13 (12),
1057–1098. https://doi.org/10.1016/S1473-3099(13)70318-9.
Li, B., Webster, T.J., 2018. Bacteria antibiotic resistance: New challenges and
opportunities for implant-associated orthopedic infections. Journal of Orthopaedic
Research® 36 (1), 22–32. https://doi.org/10.1002/jor.23656.
Lozano, C., Aspiroz, C., Rezusta, A., Gómez-Sanz, E., Simon, C., Gómez, P., Ortega, C.,
Revillo, M.J., Zarazaga, M., Torres, C., 2012. Identification of novel vga (A)-carrying
plasmids and a Tn5406-like transposon in meticillin-resistant Staphylococcus aureus
and Staphylococcus epidermidis of human and animal origin. International journal
of antimicrobial agents 40 (4), 306–312. https://doi.org/10.1016/j.ijantimicag.201
2.06.009.
Ludwig-Müller, J., 2015. Plants and endophytes: equal partners in secondary metabolite
production? Biotechnology letters 37 (7), 1325–1334. https://doi.org/10.1007/
s10529-015-1814-4.
Ma, Y.M., Liang, X.A., Zhang, H.C., Liu, R., 2016. Cytotoxic and antibiotic cyclic
pentapeptide from an endophytic Aspergillus tamarii of Ficus carica. Journal of
agricultural and food chemistry 64 (19), 3789–3793, 10.1021/acs.jafc.6b01051.
Man, S, Gao, W, Zhang, Y, Huang, L, Liu, C., 2010. Chemical study and medical
application of saponins as anti-cancer agents. Fitoterapia 81 (7), 703–714. https://
doi.org/10.1016/j.fitote.2010.06.004. Oct 1.
Mancini, S., Poirel, L., Tritten, M.L., Lienhard, R., Bassi, C., Nordmann, P., 2018.
Emergence of an MDR Klebsiella pneumoniae ST231 producing OXA-232 and RmtF
in Switzerland. Journal of Antimicrobial Chemotherapy 73 (3), 821–823. https
://doi.org/10.1093/jac/dkx428.
Manson, A.L., Cohen, K.A., Abeel, T., Desjardins, C.A., Armstrong, D.T., Barry, C.E.,
Brand, J., Chapman, S.B., Cho, S.N., Gabrielian, A., Gomez, J., 2017. Genomic
analysis of globally diverse Mycobacterium tuberculosis strains provides insights
into the emergence and spread of multidrug resistance. Nature genetics 49 (3),
395–402. https://doi.org/10.1038/ng.3767.
Martinez-Klimova, E., Rodríguez-Peña, K., Sánchez, S., 2017. Endophytes as sources of
antibiotics. Biochemical pharmacology 134, 1–17. https://doi.org/10.1016/j.
bcp.2016.10.010.
Mazumder, K., Ruma, Y.N., Akter, R., Aktar, A., Hossain, M.M., Shahina, Z.,
Mazumdar, S., Kerr, P.G., 2021. Identification of bioactive metabolites and
evaluation of in vitro anti-inflammatory and in vivo antinociceptive and antiarthritic
activities of endophyte fungi isolated from Elaeocarpus floribundus blume. Journal
of Ethnopharmacology 273 p.113975. 10.1016/j.jep.2021.113975.
Mbekou, M.I.K., Dize, D., Yimgang, V.L., Djague, F., Toghueo, R.M.K., Sewald, N.,
Lenta, B.N., Boyom, F.F., 2021. Antibacterial and mode of action of extracts from
endophytic fungi derived from Terminalia mantaly, Terminalia catappa, and
Cananga odorata. BioMed research international. 2021. 10.1155/2021/6697973.
Monowar, T., Rahman, M., Bhore, S.J., Raju, G., Sathasivam, K.V., 2018. Silver
nanoparticles synthesized by using the endophytic bacterium Pantoea ananatis are
promising antimicrobial agents against multidrug resistant bacteria. Molecules 23
(12), 3220, 10.3390/molecules23123220.
Nisa, H., Kamili, A.N., Nawchoo, I.A., Shafi, S., Shameem, N., Bandh, S.A., 2015. Fungal
endophytes as prolific source of phytochemicals and other bioactive natural
products: a review. Microbial pathogenesis 82, 50–59. https://doi.org/10.1016/j.
micpath.2015.04.001.
Ngo, L.T., Okogun, J.I., Folk, W.R., 2013. 21st century natural product research and drug
development and traditional medicines. Natural product reports 30 (4), 584–592.
https://doi.org/10.1039/c3np20120a.
Nguyen, Q.H., Nguyen, H.V., Vu, T.H.N., Chu-Ky, S., Vu, T.T., Hoang, H., Quach, N.T.,
Bui, T.L., Chu, H.H., Khieu, T.N., Sarter, S., 2019. Characterization of endophytic
Streptomyces griseorubens MPT42 and assessment of antimicrobial synergistic
interactions of its extract and essential oil from host plant Litsea cubeba. Antibiotics
8 (4), 197, 10.3390/antibiotics8040197.
Olaitan, A.O., Morand, S., Rolain, J.M., 2014. Mechanisms of polymyxin resistance:
acquired and intrinsic resistance in bacteria. Frontiers in microbiology 5, 643.
https://doi.org/10.3389/fmicb.2014.00643.
Passari, A.K., Mishra, V.K., Saikia, R., Gupta, V.K., Singh, B.P., 2015. Isolation,
abundance and phylogenetic affiliation of endophytic actinomycetes associated with
medicinal plants and screening for their in vitro antimicrobial biosynthetic potential.
Frontiers in microbiology 6, 273. https://doi.org/10.3389/fmicb.2015.00273.
Radić, N., Štrukelj, B., 2012. Endophytic fungi—The treasure chest of antibacterial
substances. Phytomedicine 19 (14), 1270–1284. https://doi.org/10.1016/j.
phymed.2012.09.007.
Ramírez-Vargas, G., Quesada-Gómez, C., Acuña-Amador, L., López-Ureña, D., Murillo, T.,
del Mar Gamboa-Coronado, M., Chaves-Olarte, E., Thomson, N., Rodríguez-
Cavallini, E., Rodríguez, C., 2017. A Clostridium difficile lineage endemic to Costa
Rican hospitals is multidrug resistant by acquisition of chromosomal mutations and
novel mobile genetic elements. Antimicrobial agents and chemotherapy 61 (4).
https://doi.org/10.1128/AAC.02054-16 pp. e02054-16.
Ramesh, V., Arivudainambi, U.S.E., Rajendran, A., 2017. The molecular phylogeny and
taxonomy of endophytic fungal species from the leaves of Vitex negundo L. Studies
in Fungi 2 (1), 26–38. https://doi.org/10.5943/stif/2/1/4.
Ranjani, S., Shariq Ahmed, M., MubarakAli, D., Ramachandran, C., Senthil Kumar, N.,
Hemalatha, S., 2020. Toxicity assessment of silver nanoparticles synthesized using
endophytic fungi against nosacomial infection. Inorg. Nano-Met. Chem 51 (8),
1080–1085. https://doi.org/10.1080/24701556.2020.1814332.
P. Pasrija et al.
Redgrave, L.S., Sutton, S.B., Webber, M.A., Piddock, L.J., 2014. Fluoroquinolone
resistance: mechanisms, impact on bacteria, and role in evolutionary success. Trends
in microbiology 22 (8), 438–445. https://doi.org/10.1016/j.tim.2014.04.007.
Roy, A., 2017. A review on the alkaloids an important therapeutic compound from
plants. IJPB 3 (2), 1–9. https://doi.org/10.37628/ijpb.v3i2.199.
Rushton-Green, R., Darnell, R.L., Taiaroa, G., Carter, G.P., Cook, G.M., Morgan, X.C.,
2019. Agricultural origins of a highly persistent lineage of vancomycin-resistant
Enterococcus faecalis in New Zealand. Applied and environmental microbiology 85
(13), e00137–19. https://doi.org/10.1128/AEM.00137-19.
Saxena, S., Meshram, V., Kapoor, N., 2015. Muscodor tigerii sp. nov.-Volatile antibiotic
producing endophytic fungus from the Northeastern Himalayas. Annals of
microbiology 65 (1), 47–57. https://doi.org/10.1007/s13213-014-0834-y.
Sharaf, MH, Abdelaziz, AM, Kalaba, MH, Radwan, AA, Hashem, AH., 2021.
Antimicrobial, Antioxidant, Cytotoxic Activities and Phytochemical Analysis of
Fungal Endophytes Isolated from Ocimum Basilicum. Applied biochemistry and
biotechnology 1–9. https://doi.org/10.1007/s12010-021-03702-w. Oct 18.
Sharifi-Rad, M., Nazaruk, J., Polito, L., Morais-Braga, M.F.B., Rocha, J.E., Coutinho, H.D.
M., Salehi, B., Tabanelli, G., Montanari, C., del Mar Contreras, M., Yousaf, Z., 2018.
Matricaria genus as a source of antimicrobial agents: From farm to pharmacy and
food applications. Microbiological research 215, 76–88, 10.1016/j.
micres.2018.06.010.
Sharma, A., Kaur, R., Kaur, J., Garg, S., Bhatti, R., Kaur, A., 2021. An endophytic
Schizophyllum commune Fr. exhibits in-vitro and in-vivo antidiabetic activity in
streptozotocin induced diabetic rats. AMB Express 11 (1), 1–11. https://doi.org/
10.1186/s13568-021-01219-3.
Singh, D., Rathod, V., Ninganagouda, S., Hiremath, J., Singh, A.K., Mathew, J., 2014.
Optimization and characterization of silver nanoparticle by endophytic fungi
Penicillium sp. isolated from Curcuma longa (turmeric) and application studies
against MDR E. coli and S. aureus. Bioinorganic chemistry and applications. https://
doi.org/10.1155/2014/408021. 2014.
Sivasankaridevi, T., Rajan, A., Maina, C.C., Suvarna, V.C., 2013. Antimicrobial activity of
some important edible leaf extracts. Insight Microbiology 3 (2), 15–18. https://doi.
org/10.5567/IMICRO-IK.2013.15.18.
Soto, S.M., 2013. Role of efflux pumps in the antibiotic resistance of bacteria embedded
in a biofilm. Virulence 4 (3), 223–229. https://doi.org/10.4161/viru.23724.
Strobel, G., 2018. The emergence of endophytic microbes and their biological promise.
Journal of Fungi 4 (2), 57, 10.3390/jof4020057.
Sun, J., Chen, F., Braun, C., Zhou, Y.Q., Rittner, H., Tian, Y.K., Cai, X.Y., Ye, D.W., 2018.
Role of curcumin in the management of pathological pain. Phytomedicine 48,
129–140, 10.1016/j.phymed.2018.04.045.
Taechowisan, T., Chanaphat, S., Ruensamran, W., Phutdhawong, W.S., 2014.
Antibacterial activity of new flavonoids from Streptomyces sp. BT01; an endophyte
in Boesenbergia rotunda (L.) Mansf. Journal of Applied Pharmaceutical Science 4
(4), 8. https://doi.org/10.7324/JAPS.2014.40402.
Tagliaferri, T.L., Guimarães, N.R., Pereira, M.D.P.M., Vilela, L.F.F., Horz, H.P., Dos
Santos, S.G., Mendes, T.A.D.O., 2020. Exploring the potential of CRISPR-Cas9 under
challenging conditions: facing high-copy plasmids and counteracting beta-lactam
resistance in clinical strains of Enterobacteriaceae. Frontiers in Microbiology 11,
578, 10.3389/fmicb.2020.00578.
Tanwar, J., Das, S., Fatima, Z., Hameed, S., 2014. Multidrug resistance: an emerging
crisis. Interdisciplinary perspectives on infectious diseases. https://doi.org/10.1155/
2014/541340. 2014.
Taufiq, M.M.J., Darah, I., 2019. Antibacterial activity of an endophytic fungus
Lasiodiplodia pseudotheobromae IBRL OS-64 residing in leaves of a medicinal herb,
Ocimum sanctum Linn. Journal of Applied Biology and Biotechnology 7 (2). https://
doi.org/10.7324/JABB.2019.70207, 3-1.
Tejesvi, M.V., Segura, D.R., Schnorr, K.M., Sandvang, D., Mattila, S., Olsen, P.B.,
Neve, S., Kruse, T., Kristensen, H.H., Pirttilä, A.M., 2013. An antimicrobial peptide
from endophytic Fusarium tricinctum of Rhododendron tomentosum Harmaja.
Fungal Diversity 60 (1), 153–159. https://doi.org/10.1007/s13225-013-0227-8.
10
Phytomedicine Plus 2 (2022) 100249
Tiwari, R, Rana, CS., 2015. Plant secondary metabolites: a review. International Journal
of Engineering Research and General Science 3 (5), 661–670. Sep. https://www.res
earchgate.net/publication/282733096_Plant_secondary_metabolites_a_review.
Tungmunnithum D, Thongboonyou A, Pholboon A, Yangsabai A. Flavonoids and other
phenolic compounds from medicinal plants for pharmaceutical and medical aspects:
An overview. Medicines. 2018 Sep;5(3):93. 10.3390/medicines5030093.
Trenado-Uribe, M., Silva-Miranda, M., Rivero-Cruz, J.F., Rodríguez-Peña, K., Espitia-
Pinzón, C.I., Rodríguez-Sanoja, R., Sánchez, S., 2018. Antimycobacterial activity of
an anthracycline produced by an endophyte isolated from Amphipterygium
adstringens. Molecular biology reports 45 (6), 2563–2570. https://doi.org/10.100
7/s11033-018-4424-0.
Uabundit, N., Wattanathorn, J., Mucimapura, S., Ingkaninan, K., 2010. Cognitive
enhancement and neuroprotective effects of Bacopa monnieri in Alzheimer’s disease
model. Journal of ethnopharmacology 127 (1), 26–31. https://doi.org/10.1016/j.
jep.2009.09.056.
Ukwatta, K.M., Lawrence, J.L., Wijayarathna, C.D., 2019. The study of antimicrobial,
anti-cancer, anti-inflammatory and α-glucosidase inhibitory activities of
Nigronapthaphenyl, isolated from an extract of Nigrospora sphaerica. Mycology 10
(4), 222–228. https://doi.org/10.1080/21501203.2019.1620892.
Vora, J., Velhal, S., Sinha, S., Patel, V., Shrivastava, N., 2021. Bioactive phytocompound
mulberroside C and endophytes of Morus alba as potential inhibitors of HIV-1
replication: a mechanistic evaluation. HIV medicine 22 (8), 690–704. https://doi.
org/10.1111/hiv.13116.
Vu, T.H.N., Nguyen, Q.H., Le, T.T.H., Chu-Ky, S., Phi, Q.T., 2019. Optimal fermentation
conditions for antibiotic production by endophytic streptomyces cavourensis ybq59
isolated from Cinnamomum cassia Presl. Vietnam Journal of Science and Technology
57 (3B), 144. https://doi.org/10.15625/2525-2518/57/3B/14501.
Weaver, BA., 2014. How Taxol/paclitaxel kills cancer cells. Molecular biology of the cell
25 (18), 2677–2681. Sep 1510.1091/mbc.e14-04-0916.
World Health Organization, 2019. 2019 antibacterial agents in clinical development: an
analysis of the antibacterial clinical development pipeline. https://apps.who.int/iri
s/bitstream/handle/10665/330420/9789240000193-eng.pdf. (accessed 21
November, 2021).
Wright, M.S., Suzuki, Y., Jones, M.B., Marshall, S.H., Rudin, S.D., van Duin, D., Kaye, K.,
Jacobs, M.R., Bonomo, R.A., Adams, M.D., 2015. Genomic and transcriptomic
analyses of colistin-resistant clinical isolates of Klebsiella pneumoniae reveal
multiple pathways of resistance. Antimicrobial agents and chemotherapy 59 (1),
536–543. https://doi.org/10.1128/AAC.04037-14.
Yahara, K., Nakayama, S.I., Shimuta, K., Lee, K.I., Morita, M., Kawahata, T., Kuroki, T.,
Watanabe, Y., Ohya, H., Yasuda, M., Deguchi, T., 2018. Genomic surveillance of
Neisseria gonorrhoeae to investigate the distribution and evolution of antimicrobial-
resistance determinants and lineages. Microbial genomics (8), 4. https://doi.org/
10.1099/mgen.0.000205.
Yenn, T.W., Ibrahim, D., Chang, L.K., Ab Rashid, S., Ring, L.C., Nee, T.W., Noor, M.I.B.
M., 2017. Antimicrobial efficacy of endophytic Penicillium purpurogenum ED76
against clinical pathogens and its possible mode of action. Korean Journal of
Microbiology 53 (3), 193–199. https://doi.org/10.7845/kjm.2017.7022.
Zaher, A.M., Makboul, M.A., Moharram, A.M., Tekwani, B.L., Calderón, A.I., 2015.
A new enniatin antibiotic from the endophyte Fusarium tricinctum Corda. The
Journal of antibiotics 68 (3), 197–200, 10.1038/ja.2014.129.
Zargar, M., Hamid, A.A., Bakar, F.A., Shamsudin, M.N., Shameli, K., Jahanshiri, F.,
Farahani, F., 2011. Green synthesis and antibacterial effect of silver nanoparticles
using Vitex negundo L. Molecules 16 (8), 6667–6676. https://doi.org/10.3390/
molecules16086667.
Zin, N.M., Baba, M.S., Zainal-Abidin, A.H., Latip, J., Mazlan, N.W., Edrada-Ebel, R.,
2017. Gancidin W, a potential low-toxicity antimalarial agent isolated from an
endophytic Streptomyces SUK10. Drug Design. Development and Therapy 11, 351.
https://doi.org/10.2147/DDDT.S121283.
Zhou, J., Liu, Z., Wang, S., Li, J., Li, Y., Chen, W.K., Wang, R., 2020. Fungal endophytes
promote the accumulation of Amaryllidaceae alkaloids in Lycoris radiata.
Environmental microbiology 22 (4), 1421–1434. https://doi.org/10.1111/1462-
2920.14958.