Review

pubs.acs.org/jnp

Antibacterial Compounds from Marine Bacteria, 2010−2015

Claudia Schinke,*,† Thamires Martins,† Sonia C. N. Queiroz,‡ Itamar S. Melo,‡
and Felix G. R. Reyes†
†
Department of Food Science, School of Food Engineering, University of Campinas, Campinas-SP, CEP 13083-862, Brazil
‡
Brazilian Agricultural Research Corporation, Rodovia SP-340 km 127.5, Jaguariúna-SP, CEP 13820-000, Brazil

ABSTRACT: This review summarizes the reports on antibacterial com-

pounds that have been obtained from marine-derived bacteria during the
period 2010−2015. Over 50 active compounds were isolated during this
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period, most of which (69%) were obtained from Actinobacteria. Several

compounds were already known, such as etamycin A (11) and nosiheptide
(65), and new experiments with them showed some previously undetected
antibacterial activities, highlighting the fact that known natural products may
be an important source of new antibacterial leads. New broad-spectrum
antibacterial compounds were reported with activity against antibiotic resistant
Gram-positive and Gram-negative bacteria. Anthracimycin (33), kocurin (66),
gageotetrins A−C (72−74), and gageomacrolactins 1−3 (86−88) are examples of compounds that display promising properties
and could be leads to new antibiotics. A number of microbes produced mixtures of metabolites sharing similar chemical scaffolds,
and structure−activity relationships are discussed.

■ INTRODUCTION
The Centers for Disease Control and Prevention estimated that
there were approximately 23 000 deaths due to resistant bacterial
infections in the USA in 2013.1 According to the World Health
Organization (WHO),2 there were nearly half a million new
victims of multidrug-resistant tuberculosis (MDR-TB) in 2013,
and 100 countries reported cases of extensively drug-resistant
tuberculosis (XDR-TB). The WHO also reported that last resort
medicines, such as third-generation cephalosporins, have failed
to cure cases of gonorrhea in 10 countries. In addition, an
editorial by Rice3 in 2008 nominated a small group of bacteria
that “escape the lethal action of antibiotics” as the “the ESKAPE
bugs”Enterococcus faecium, Staphylococcus aureus, Klebsiella
pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa,
and Enterobacter speciesand called attention to the threat of
antibiotic-resistant Gram-negative bacteria. He noted that “the
ESKAPE bugs are extraordinarily important, not only because
they cause the lion’s share of nosocomial infections but also
because they represent paradigms of pathogenesis, transmission,
and resistance”. In 2010, the Infectious Diseases Society of
America (IDSA) started the “10 × ’20 Initiative”, with the aim of
developing a global venture for antibiotics research and
development focused on launching 10 new antibacterial drugs
that are effective and safe for systemic administration by 2020.4
Periodic updates on antibacterial compounds in clinical trial have
been published.5,6 In the latest report, the authors voiced concern
over the lack of advance in new drugs active against MDR Gram-
negative infections. As noted in the above-mentioned reports,
many standard medical procedures will prove to be futile if no
efficient anti-infective treatment is available. The development of
new antibiotics is among the core actions that will help fight these
deadly infections.
© 2017 American Chemical Society and
American Society of Pharmacognosy
Toward the aim of discovering new molecules displaying
antibacterial properties, researchers around the world have
dedicated time and effort to looking for novel sources (animals,
microbes, and plants) in varied environments, including thermal
springs, Antarctica, caves, seas, and deserts, to mention a few,
from which to draw antibiotic leads.7 For several decades, the
marine environment has been drawing attention, as many new
compounds showing potent antibacterial activities have been
discovered from bacteria residing on or in molluscs, algae,
sediments, water, and corals.8−10 Researchers are still investigat-
ing the associations that occur among microbes, their hosts, and
the individuals of the community sharing that habitat. However,
from results already obtained, it is becoming evident that these
associations involve the sharing of complex chemical signals,
depending on whether they are competitive11 or mutually
advantageous.10,12 The purpose of these signaling molecules
appears to be fighting off competitors by killing or hindering their
settlement.
These antagonist compounds, especially those displaying new
chemical scaffolds, present a much desired opportunity to
discover new antibiotics with which to confront multiresistant
bacteria. As early as the 1940s and 1950s, marine bacteria were
shown to produce antimicrobial compounds. The 1960s saw the
first marine bacterial metabolites identified,13 and the 1970s saw
their antibiotic properties reported.14 Reviews on antibacterial
compounds obtained from marine-derived bacteria have been
published since the 1990s.14−17 More recently, such reports have
emphasized molecules against methicillin-resistant Staphylococ-
cus aureus (MRSA) and vancomycin-resistant enterococci
(VRE),18,19 peptides,9,20 and lanthipeptides,21 as well as
Received: March 15, 2016
Published: March 31, 2017
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Journal of Natural Products Review

Table 1. Class of Marine Bacteria from Which Antibacterial Compounds Were Reported during 2010−2015
total number of active new new compounds active against Gram-negative known compounds with novel
class compounds compounds bacteria activity
Actinobacteria 36 27 7 9
Bacilli 12 12 12
Gammaproteobacteria 4 3 3 1
total 52 42 22 10

compounds isolated from actinobacteria (covering 1999−

2009)22 or from diverse microorganisms encompassing several
chemical classes.23
Due to the fast evolving number of works published yearly on
the subject, we thought it important to review those published
from 2010 to 2015. In the present review, only compounds
displaying minimum inhibitory concentrations (MICs) less than
or equal to 20 μg mL−1 were selected from the literature. This
criterion is a compromise between the stringent end point
recommended for Gram-positive (<1−10 μM) and the more
flexible cutoff for Gram-negative (10−100 μM) bacteria.24
Where MICs were expressed in molar values, the concentration
was converted using the reported molecular mass, thus allowing
the direct comparison of activities among several compounds.
The majority of the identified compounds were isolated from
Actinobacteria and Bacilli (Table 1). Interestingly, a higher
number of new molecules that were active against Gram-negative
bacteria were reported from Bacilli. Additionally, known
compounds displaying novel antibacterial activity accounted
for approximately 20% of the reported active compounds.
Marine environments from several countries were sampled in Figure 2. New antibacterial compounds isolated from marine bacteria
search of new bioactive bacterial genera. A significant number of according to bacterial class and sampling substrate.
the new molecules (Figure 1) were obtained from bacteria
sampled in China and South Korea (38% and 17%, respectively). 005, and methicillin-resistant S. aureus (MRSA) ATCC43300,
with MICs ≤ 1.0 μg mL−1. However, these bacterial strains were
less affected by compounds 3 and 4. The authors speculate that
the higher potency of 1 and 2 could be explained by the nitrogen-
and oxygen-containing pentacycle, which is absent from
compounds 3 and 4 and is analogous to the oxazolidinones, a
class of antibiotics commercially available.

Figure 1. Sampling sites of marine bacteria from which new and known
antibacterial compounds were reported during 2010−2015.

Microbes were isolated from several substrates, including

water, sediment, algae, sponge, and corals, as well as from
gorgonians and mussels (Figure 2).

■ ANTIMICROBIAL AGENTS FROM ACTINOBACTERIA

Family Streptomycetaceae. Streptomyces caelestis was
obtained from the waters of the Red Sea, off the coast of Jeddah,
Saudi Arabia,25 and produced new polycyclic xanthones,
citreamicin θ A (1), citreamicin θ B (2), citreaglycon A (3),
and dehydrocitreaglycon A (4). Diastereomers 1 and 2 displayed A known cyclic peptide griseoviridin (5) was obtained from
comparable inhibition of Staphylococcus haemolyticus Streptomyces roseogilvus var. marine strain L0804, isolated from
UST950701-004, Bacillus subtillis 769, S. aureus UST950701- mud samples collected at Lian Yun Harbor, Jiangsu Province,
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China.26 The MICs for S. aureus ATCC25925, B. subtilis
ATCC63501, and drug-resistant S. aureus varied between 8 and
16 μg mL−1, which were similar to those of cefradine, the positive
control. The MICs were higher for P. aeruginosa ATCC25916,
Escherichia coli ATCC25922, and drug-resistant E. coli (32 μg
mL−1). This is the first report of 5 being isolated from a marine
microorganism.
The crude extract obtained from the cells of Streptomyces
f radiae strain PTZ0025,27 isolated from marine sediment,
provided polyene acids and capoamycin-type antibiotics: the
new compounds fradic acids A (6) and B (7) and fradimycins A
(8) and B (9) and the known compound MK844-mF10 (10).
Antibacterial assays against S. aureus with compounds 8, 9, and
10 showed MICs between 2 and 6 μg mL−1. Compounds 6 and 7
displayed no bioactivity.
The known streptogramin etamycin A (11) was isolated from
Streptomyces strain CNS-575 obtained from the sediments of the
Nasese shoreline, Viti Levu, coast of Fiji.28 The MICs of the
compound for community-associated MRSA (CA-MRSA)
strains and some hospital-associated MRSA (HA-MRSA) strains
were 1−2 μg mL−1. Streptococcus pyogenes and Streptococcus
agalactiae were sensitive to the compound (8 μg mL−1);
however, its activity was poor against Enterococcus faecalis
(MIC 16 μg mL−1). Compound 11 was also active against the
Gram-negative respiratory tract pathogens Moraxella catarrhalis
(MIC 1 μg mL−1) and Haemophilus inf luenzae (MIC 16 μg
mL−1) but was inactive against E. coli ATCC25922, P. aeruginosa
ATCC27853, and Salmonella typhimurium ATCC13311. Mice
systemically infected with MRSA Sanger 252 showed a decrease
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in symptom intensity after the administration of 11. The authors
hypothesized that 11 may inhibit MRSA due to protein synthesis
inhibition similar to the combination of streptogramins
quinupristin−dalfopristin (Synercid), in which quinupristin
prevents polypeptide elongation and dalfopristin induces 50S
ribosomal conformational changes. However, unlike quinupris-
tin−dalfopristin, 11 displays anti-MRSA activity on its own
without the synergistic effect of a streptogramin partner. It is the
first description of 11 obtained from a marine microbe.
Another study on the same Streptomyces sp. strain CNS-575
resulted in the discovery of the new depsipeptides fijimycins A−
C (12−14), as well as 11.29 Compounds 11 and 12 are
stereoisomers bearing a D-α-phenylsarcosine structure. The cis
and trans isomers of the 4-hydroxyproline peptide bonds in 11
and 12 might be responsible for the equilibrium mixture of
conformers revealed by 1H NMR studies. The hospital-
associated MRSA strains ATCC33591 and Sanger 252 and the
community-associated strain MRSA UAMS1182 were sensitive
to 11 and 12 (4−16 μg mL−1) but not to 13 and 14. The α-
phenylsarcosine moiety seems to be essential for significant
antibacterial activity, whether in the D- or L-conformation, as
revealed by the similar potencies of 11 and 12.
Sea sediment samples collected in British Columbia, Canada,
resulted in the isolation of 186 Streptomyces strains.30 Ethyl
acetate extracts of the isolates in antimicrobial disc diffusion
assays against P. aeruginosa (ATCC27853), E. coli (UBC 8161),
MRSA (ATCC33591), B. subtilis (H344), and Mycobacterium
fortuitum revealed 47 strains that were active against at least two
of the microorganisms. Four of these extracts that showed the
strongest antimicrobial activities were chemically analyzed,
which led to the isolation of novobiocin analogues and
dilactones. The newly identified compounds included desme-
thylnovobiocin (15), 5-hydroxynovobiocin (16), desmethyldes-
carbamoyl-5-hydroxynovobiocin (17), and desmethyl-5-hydrox-
ynovobiocin (18). Also found were the known novobiocin (19)
and desmethyldescarbamoylnovobiocin (20). The MICs for
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pure compounds against MRSA were 0.25 μg mL−1 (19), 8−16
μg mL−1 (15 and 16), and >64 μg mL−1 (17, 18, and 20).
Structure−activity analysis highlighted the importance of the
C4″ and C3″ components (OMe and carbamoyl) of the
novobiose along with the hydroxy at C5 of the hydroxybenzoate
moiety for the inhibition of MRSA. Substitution with other
moieties at these positions caused a complete loss of inhibitory
activity.
Streptomyces sp. strain MS100061 isolated from a South China
Sea sediment produced spirotetronates, the new lobophorin G
(21), and the known lobophorins A (22) and B (23).31
Mycobacterium bovis BCG (Pasteur 1173P2) was highly sensitive
to these lobophorins (MICs 0.8−1.5 μg mL−1); however,
Mycobacterium tuberculosis H37Rv (ATCC27294) demanded
higher MICs (16−32 μg mL−1). The compounds were also active
against B. subtilis ATCC6663 (MICs 1.5−12 μg mL−1).
Compounds 21−23 were ineffective against S. aureus
ATCC29213, MRSA, and P. aeruginosa ATCC27853. Struc-
ture−activity analysis indicated the amide-saccharide moiety in
23 to be essential for mycobacteria inhibition. In addition, 21 and
22 differ only by the presence of an acetyl group in the latter,
which does not influence antimycobacterial potency but greatly
increases the activity against B. subtilis. According to the authors,
this is the first report of the inhibition of M. bovis BCG and
M. tuberculosis H37Rv by lobophorins.
Lobophorins were also obtained from Streptomyces sp. strain
12A35, which was recovered from a deep sea sediment from the
South China Sea.32 Bioassay-guided purification led to the
isolation of new lobophorins H (24) and I (25) and the known
lobophorin F (26) and 23. Compounds 24, similar to the positive
control ampicillin, and 23 showed strong inhibition of B. subtilis
CMCC63501 (MICs 1.6−3.1 μg mL−1). Compounds 24 and 26
exhibited limited activity against S. aureus ATCC29213 (MICs of
6.2−50 μg mL−1). Compound 25 displayed no activity, and none
of the isolated compounds inhibited E. coli ATCC25922.
According to the authors, the increase in the number of
monosaccharide units attached to the spirotetronate skeleton (4
units in compound 24) increased the inhibitory activity, which
indicated that the chain length influences the antibacterial
potency of lobophorins by specifically interacting with the yet
unknown biological target.
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Streptomyces avermitilis strain MS449,33 recovered from a
South China Sea sediment, produced chromopeptide lactones,
the known actinomycin D (27), actinomycin X2 (28), and
actinomycin X0β (29) in high concentrations. Pure compounds
27−29 were active against Mycobacterium bovis BCG (Pasteur
1173P2), with MICs of 0.2−0.5 μg mL−1, and Mycobacterium
tuberculosis (MTB) H37Rv (ATCC27294) with MIC values
between 1 and 8 μg mL−1. The authors report that wild
S. avermitilis MS449 is the first strain to simultaneously produce
high quantities of 27−29 under nonoptimized conditions (0.15,
1.92, and 1.77 mg mL−1, respectively). The authors note that, in
contrast to 27, which is a well-known therapeutically used drug,
MTB H37Rv was more susceptible to 28.
Streptomyces sundarbansensis MS1/7, isolated from brown
marine algae collected on the Bejaia coastline, Algeria, produced
a new phaeochromycin analogue compound, 2-hydroxy-5-[(6-
hydroxy-4-oxo-4H-pyran-2-yl)methyl]-2-propylchroman-4-one
(30), and the known phaeochromycin C (31) and phaeochro-
mycin E (32).34,35 Pure compound 30 was bacteriostatic against
MRSA ATCC43300 (MIC 2 μg mL−1) but not against S. aureus
ATCC25923. E. coli ATCC25922 was also inhibited but at a
higher concentration (MIC 16 μg mL−1). Compounds 31 and 32
were ineffective against the bacteria tested. According to the
authors, the bacteriostatic activity against MRSA and failure to
inhibit S. aureus ATCC25923 are similar to the activity of
epicatechin gallate, a molecule that interferes with the genes that
are selectively involved in oxacillin or methicillin resistance in
S. aureus. This suggests that the anti-MRSA activity of compound
30 may be due to the inhibition of the production of the
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penicillin-binding proteins (PBP2′) involved in cell wall
synthesis.
The structure of the polyketide anthracimycin (33) is unique
in that it does not show similarity to any reported antibacterial
natural products. The compound was obtained from Streptomyces
strain CNH365, which was isolated from marine sediments
collected in Santa Barbara, CA, USA.36 Compound 33 potently
inhibited B. anthracis (strain UM23C1-1) with an MIC of 0.03 μg
mL−1 in a microplate assay. Other bacteria that were sensitive to
the compound were S. aureus ATCC13709, E. faecalis
ATCC29212, and Streptococcus pneumoniae ATCC51916, with
MICs between 0.06 and 0.25 μg mL−1. However, poor activity
was detected against E. coli MCR106 imp, E. coli MG1655 tolC,
H. inf luenzae ATCC 31517, H. inf luenzae ATCC31517 KO,
Burkholderia thailandensis E264 KO, and P. aeruginosa PAO1 KO.
The authors note that 33 provided a 90% survival rate at 10 mg
kg−1 in MRSA intraperitoneally infected CD1 mice. The
synthetic C-4 dichloro derivative displayed higher activity against
the Gram-negative pathogens, suggesting that small structural
changes in the molecule may lead to new antibacterial
compounds.
Another study on 33 also obtained from Streptomyces
CNH36537 demonstrated that not only several MSSA and
MRSA strains and vancomycin-resistant S. aureus (MIC ≤ 0.25
μg mL−1) but also Gram-negative M. catarrhalis (MIC 4 μg
mL−1) were susceptible to the compound. However, other
pathogens such as P. aeruginosa, K. pneumoniae, and A. baumannii
were insensitive. Not only did it exhibit rapid killing kinetics, but
the in vitro data suggested that 33 also affected MRSA at sub-
MIC levels. Sub-MIC conditions slowed MRSA growth and
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improved the antibacterial activity of human cathelicidin, a family
of antimicrobial polypeptides present in macrophages and
polymorphonuclear leukocytes. The improved activity of
cathelicidin persisted, despite a reduction in the bactericidal
effect of 33 in the presence of 20% human serum.
A rare hybrid terpenoid/polyketide biosynthetic pathway may
be responsible for the production of meroterpenoids obtained
from Streptomyces sp. strain SCSIO 10428 isolated from a
Xieyang Island sediment sample, in Beihai, Guangxi Province,
China.38 The compounds obtained included the new 4-dehydro-
4a-dechloronapyradiomycin A1 (34), 3-chloro-6,8-dihydroxy-8-
α-lapachone (35), 3-dechloro-3-bromonapyradiomycin A1 (36),
and the known analogues napyradiomycins A1 (37), 18-
oxonapyradiomycin A1 (38), napyradiomycins B1 (39), B3
(40), and SR (41), and naphthomevalin (42). Tested against
S. aureus ATCC29213, B. subtilis SCSIO BS01, and Bacillus
thuringiensis SCSIO BT01, strong inhibition activities were
displayed by 40 (MIC ≤ 0.5 μg mL−1) and 36 (MIC ≤ 1 μg
mL−1) and to a lesser extent by compounds 37, 39, and 42 with
MICs ≤ 2 μg mL−1. Compounds 34, 35, and 38 were weakly
active against these bacteria (MICs 4−32 μg mL−1). None
inhibited E. coli, and compound 41 showed no antibacterial
activity. Structure−activity relationships revealed that oxidation
at C-17 (38), the presence at C-10a of a linear 10-carbon
monoterpenoid subunit (36 and 37), and a cyclized six-
membered ring (39 and 40) or 14-membered ring (41) had a
strong impact on the antibacterial activity of these unusually
halogenated meroterpenoids.
Streptomyces scopuliridis SCSIO ZJ46,39 isolated from a deep-
sea sediment from the South China Sea, produced cyclo-
hexapeptides, including the new desotamides B−D (43−45) and
the known desotamide A (46), cyclo-(-Trp-Gly-Asn-Ile-Leu-
Leu-). Compounds 43 and 46, in which the Trp moiety is
preserved, displayed antibacterial activity against S. aureus
ATCC29213, S. pneumoniae NCTC 7466, and clinical
methicillin-resistant Staphylococcus epidermidis (MRSE) shhs-
E1 with MICs between 12 and 32 μg mL−1. However, no
inhibition was detected against K. pneumoniae ATCC13883 and
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MRSA shhs-A1. Compounds 44 and 45, in which the Trp is

cleaved either by oxidation (44) or by the loss of a carbon (45),
displayed no antibacterial activity against any pathogen tested.
These findings highlight the necessity of the integrity of the Trp
moiety for inhibitory activity. According to the authors, clues to
the biosynthetic relationships among the four metabolites are
provided by the higher proportion obtained of compound 46,
with 43−45 being minor products. They speculate that
postassembly line oxidation of the Trp in compound 46 by the
Trp-2,3-dioxygenase of S. scopuliridis SCSIO ZJ46 generates
compound 44, and compound 45 might be the result of NFK (N-
formylkynurenine residue) deformylation in compound 44.

Isolated from marine sediment from Utonde, Equatorial

Guinea, the Streptomyces zhaozhouensis strain CA185989
produced three new polycyclic tetramic acid macrolactams,40
including the new isoikarugamycin (47), 28-N-methylikaruga-
mycin (48), and 30-oxo-28-N-methylikarugamycin (49). The
bioactivities of compounds 47−49 were compared to that of
known ikarugamycin (50). Compounds 47, 48, and 50 strongly
inhibited MRSA (MICs 1−4 μg mL−1), whereas compound 49
was inactive (MIC 32−64 μg mL−1). None of the compounds
inhibited E. coli even at 64 μg mL−1. Structure−activity analysis
revealed that methylation of the nitrogen atom of the tetramic
acid moiety, as in 48, had no impact on its antibacterial activity.
However, the ethyl group side chain (C-16) is crucial for the
bioactivity of this family of compounds. Its oxidation to a
carbonyl, as in 49, severely decreased its antibacterial activity.
New streptophenazines I (51), J (52), and K (53), along with
other streptophenazines, were detected in culture extracts of
Streptomyces sp. strain HB202 isolated from a sponge from the
Baltic Sea.41 The antibacterial activities of compounds 51−53
were compared with those of streptophenazine G (54), which is a
known representative of this class of molecules. Compounds 54
and 53 showed activity against B. subtilis (IC50 of 3.6 and 9.1 μg
mL−1, respectively) and S. epidermidis (IC50 of 3.6 and 6.1 μg
mL−1, respectively). Compounds 51 and 52 showed no
bioactivity. The authors report that the UV chromatogram of
an ethyl acetate extract of the culture broth from a single strain
showed a large number of peaks that indicated the presence of
more than 20 phenazine derivatives in a single fermentation.
They commented that this biological derivatization, a common
feature of microbially produced antibacterial agents, facilitates
structure−function analysis without the need for chemical
synthesis experiments.
Streptomyces sp. was isolated from a marine sediment sample
from Chuuk, Federated States of Micronesia, and produced new
1220
glycosylated macrolactins A1 (55) and B1 (56) as well as the
known surfactant lauramide diethanolamine (57).42 The three
compounds inhibited B. subtillis, E. coli, P. aeruginosa, and
S. aureus with MICs of 0.02−0.13 μg mL−1, but were not as
potent as azithromycin. The chemical structure of the bio-
logically active surfactant is unusual in nature and differs from
known antimicrobial agents. This is the first report on its
antibacterial activity. The weaker activity of 55 and 56 compared
to the corresponding free −OH at C-7 is probably explained by
the presence of the sugar at C-7 on both molecules. The authors,
however, speculate that the higher solubility in polar solvents of
sugar-containing macrolactins could be an advantage.
New buanmycin (58) and buanquinone (59), pentacyclic
xanthones, were obtained from Streptomyces cyaneus isolated
from a tidal mudflat sample collected at Buan, Republic of
Korea.43 Compound 58 strongly inhibited Salmonella enterica
and B. subtilis with an MIC of 0.42 μg mL−1 for both strains.
Compound 58 was less active against S. aureus and Proteus hauseri
(MICs 6.2−12 μg mL−1). Noteworthy, it inhibited S. aureus
sortase A, a transpeptidase enzyme involved in adhesion and host
invasion by Gram-positive bacteria, more potently (IC50 value of
25 μg mL−1) than did the positive control, p-hydroxymercur-
ibenzoic acid (pHMB) (IC50 35 μg mL−1). No antibacterial
activity was detected with 59.
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Streptomyces sp. strain RL09-253-HVS-A, isolated from a
marine sediment sample from Point Estero, CA, USA, produced
known pyridyls, piericidin A1 (60) and the piericidin derivative
mer-A 2026B (61).44 The paper discusses the previously
uncharacterized activity of both compounds against the Gram-
negative bacteria type III secretion system (T3SS), which is a
virulence factor necessary for attacking host cells. T3SS
inhibitors are a new class of antibiotics known as virulence
blockers, which disarm pathogenic bacteria and prevent
infection. At 30 μg mL−1, 60 and 61 reduced the secretion of
the T3SS effector protein in Yersinia pseudotuberculosis by 65%
and 45%, respectively. The authors suggest that blocking of T3SS
does not occur by blocking bacterium−host cell interactions but
instead occurs at an earlier stage of T3SS assembly.
Collected in the Florida Keys, USA, from the surface of a
jellyfish, Streptomyces sp. CNB-091 produced the new salinamide
F (62) and the known salinamides A (63) and B (64).45 Both
Gram-positive E. faecalis and Gram-negative H. inf luenzae were
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susceptible to 62 (MIC50 12 μg mL−1). The MIC50 for cell-wall-
compromised E. coli D21f2tolC, a strain sensitive to hydrophobic
agents such as salinamides, was 0.20 μg mL−1; Neisseria
gonorrhoeae, Enterobacter cloacae, and S. aureus were not affected.
Compounds 62−64 presented strong anti-RNA-polymerase
(anti-RNAP) activity: the IC50 for S. aureus and for E. coli were
0.2−4 μM and 0.2−2 μM, respectively.46 By comparing the
structures and RNAP-inhibitory activities of 62−64, the authors
concluded that the epoxide in 63 and the chlorohydrin in 64 are
not essential to the inhibitory bioactivity.
A known thiopeptide antibiotic, nosiheptide (65), was purified
from Streptomyces sp. CNT-373 isolated from marine sediment
collected on Nacula Island, Fiji.47 The peptide displayed strong
activity against all contemporary MRSA strains resistant to
linezolid, vancomycin, and daptomycin (MICs 0.03−0.25 μg
mL−1), and the presence of 20% human serum did not hinder its
anti-MRSA bioactivity. It also inhibited clinical isolates Enter-
ococcus VRE-CUS and VRE-WMC, and M. catarrhalis
ATCC25238 (MICs 0.12, 0.12, and 0.50 μg mL−1, respectively),
as well as the contemporary hypervirulent BI/NAP1/O27 strain
of Clostridium dif f icile (MIC 0.01 μg mL−1). E. coli and
P. aeruginosa ATCC27853 were not inhibited (MIC > 4 μg
mL−1). Compound 65 significantly (P < 0.03) protected against
mortality in a murine intraperitoneal infection model with
MRSA: 10 of 10 mice were still alive on the third day of infection,
whereas 6/10 of the controls were dead on day 1. The authors
conclude that because 65 is mass produced and used as an animal
growth-promoting agent, it has an advantage over other
antimicrobials that are still in early stage research.
Family Micrococcaceae. Compound PM18110448 (later
confirmed as kocurin49) (66) was produced by Kocuria sp.
(Kocuria palustris44) obtained from a marine sponge collected at
Palk Bay, India. Compound 66 was tested against 261
microorganisms and was found to inhibit standard and clinical
isolates of S. aureus, both methicillin-sensitive and MRSA, with
MICs ranging from 0.01 to 0.50 μg mL−1; clinical and laboratory
strains of enterococci, both vancomycin-resistant (VRE) and
vancomycin-sensitive (VSE) (MICs 0.01−16 μg mL−1);
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S. epidermidis strains (MICs 0.01−1.0 μg mL−1); and several
Bacillus species (0.01−0.02 μg mL−1). However, it was ineffective
against 17 Gram-negative bacterial strains (data not shown). A
dose of 5 mg kg−1 of 66 gave 100% protection in a murine
septicemia model with MRSA strain E710 and showed
comparable efficacy to that of the front-line antibiotics linezolid
at 25 mg kg−1 and vancomycin at 150 mg kg−1 in a murine kidney
infection model with VRE.
In another study49 on 66 purified from the same microbial
species isolated from marine sponges from the Florida Keys,
USA, MRSA was sensitive to the compound with MIC values in
the submicromolar range (0.25 μg mL−1). Comparing the effect
of 66 on wild-type and thiazomycin-resistant S. aureus strains
indicated that both compounds have different modes of action.
Thiazomycin, a similar thiazolyl peptide with a 29-membered
cycle, binds to the elongation factor Tu (EF-Tu) and blocks its
tRNA/amino acyl complex binding site, thus preventing peptide
elongation by the ribosome.50 No activity of 66 was detected on
Gram-negative bacteria at 16 μg mL−1. The structure of
compound 66, synthesized by NRPS and PKS, was elucidated
through spectroscopy and chemical methods and corrects that
previously assigned to PM181104.43
Other Actinobacteria Genera. The actinomycete Pseudo-
nocardia sp. was isolated from a deep-water sediment from the
South China Sea and produced the new diazaanthraquinone
1222
Review
derivatives pseudonocardians A (67), B (68), and C (69) and
known deoxynyboquinone (70).51 Compounds 67, 68, and 70
inhibited S. aureus ATCC29213, E. faecalis ATCC 29212, and
B. thuringiensis SCSIO BT01 with MIC values in the range of 1−4
μg mL−1. Structure−activity analysis revealed that the ethyl
group at C-19, as in 68, is essential for its activity. Substitution of
this ethyl group for a methyl moiety in 67 decreases the
antibacterial activity by half. Glycosylation at C-10 in 69
prevented any inhibitory activity, similar to the inactivation
exhibited by macrolide antibiotics as a consequence of bacterial
resistance mechanisms. This is the first report on 70 obtained
from a natural source.
The Streptosporangium sp. strain DSZM 45942 isolated from a
sediment sample collected at Trondheimsfjord, Norway,
produced the known 1,6-dihydroxyphenazine-5,10-dioxide
(iodinin) (71).52 The MICs of purified 71 for E. faecium
CCUG 37832 and E. faecium CTC 492 were 0.70 and 0.35 μg
mL−1, respectively. Under laboratory conditions, the isolate
produced 0.6 g L−1 of 71, suggesting a high capacity to synthesize
phenazines. The paper discusses the biosynthetic shikimate
pathway leading from precursors erythrose 4-phosphate and
phosphoenol pyruvate to 71. The authors suggest that,
considering the wide spectrum of biological activity of 71, its
hydrophobic nature and postexcretion adherence to the cell wall
may provide an ecological advantage against competing
microorganisms.
Table 2 summarizes the activities of the compounds discussed
in this section, presenting MICs for several Gram-positive and
Gram-negative bacteria.
■
ANTIMICROBIAL METABOLITES FROM BACILLI
The bioactive B. subtillis strain 109GGC020 was isolated from a
marine sediment sample from Gageocho, Republic of Korea.53
The strain produced three new linear lipodi- and lipotetrapep-
tides named gageotetrins A−C (72−74). In broth dilution assays
on S. aureus and B. subtillis, 72−74 displayed MICs ≤ 0.02 μg
mL−1. Compounds 73 and 74 also displayed good activity on
DOI: 10.1021/acs.jnatprod.6b00235
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Table 2. Minimum Inhibition Concentration (μg mL−1) of Metabolites from Actinobacteria

compound various MRSA strains/(VRSA)a other S. aureus strains B. subtilis other bacteria ref
citreamicin θA (1) 0.25 1 0.25 0.5b 25
citreamicin θB (2) 0.25 1 0.25 0.5b
citreaglycon A (3) 8 16c 8 8b
dehydrocitreaglycon A (4) >50c 16c 8 −d
fradimycin A (8) −d 6 −d −d 27
fradimycin B (9) −d 2 −d −d
compound MK844-mF10 (10) −d 4 −d −d
etamycin A (11) 1−16c 1−2 −d 1;e 8;f 16,c,g; 16h 28, 29
fijimycin A (12) 4−32c −d −d −d 29
fijimycin C (14) 8−32c −d −d −d
lobophorin G (21) −d −d 3.1 1.6;i 32c,j 31
lobophorin A (22) −d −d 12c 1.6;i 32c,j
lobophorin B (23) −d 100c 1.6−3.1 0.8;i 16c,j 31, 32
lobophorin H (24) −d 50c 1.6 −d 32
lobophorin F (26) −d 5.2 6.2 −d
actinomycin Xθβ (27) −d −d −d 0.25;i 8j 33
actinomycin X2 (28) −d −d −d 0.25;i 1j
actinomycin D (29) −d −d −d 0.25;i 8j
anthracimycin (33) 0.06−0.16 (0.12−0.25) 0.06−0.16 −d 0.03;k 0.25;f 0.12−0.25;g 4e 36, 37
4-dehydro-4a-dechloronapyradiomycin A1 (34) −d 4 4 −d 38
3-chloro-6,8-dihydroxy-8-α-lapachone (35) −d >128c 8 −d
3-dechloro-3-bromonapyradiomycin A1 (36) −d 0.50 1 −d
napyradiomycins A1 (37) −d 1 2 −d
18-oxonapyradiomycin A1 (38) −d 32c 8 −d
napyradiomycins B1 (39) −d 1 2 −d
napyradiomycins B3 (40) −d 0.50 0.25 −d
naphthomevalin (42) −d 1 2 −d
isoikarugamycin (47) 2−4 −d −d −d 40
28-N-methylikarugamycin (48) 1−2 −d −d −d
macrolactin A1 (55) −d 0.04 0.02 0.04;l 0.13m 42
macrolactin B1 (56) −d 0.03 0.03 0.03;l; 0.13m
lauramide diethanolamine (57) −d 0.03 0.02 0.03;l 0.02m
buanmycin (58) −d 6.2 0.42 0.42;n 12h,o 43
salinamide F (62) −d −d −d 0.20m;12h; 25c,p; 50c,q 45
nosiheptide (65) 0.03−0.12 (0.06−0.12) 0.06−0.12 −d 0.01;r 0.12;g 0.50e 47
kocurin (66) 0.01−2 0.01−2 −d 0.01−1g,s 48, 49
pseudonocardian A (67) −d 4 −d 2g 51
pseudonocardian B (68) −d 2 −d 2g
deoxynyboquinone (70) −d 1 −d 1g
a
MICs presented in brackets are for vancomycin-resistant S. aureus (VRSA). bStaphylococcus hemolyticus UST950701-004. cCompound inactive on
some or all strains tested. dMIC values not available. eMoraxella catarrhalis ATCC 25238. fStreptococcus spp. gDrug-resistant Enterococcus spp.. hH.
inf luenzae. iMycobacterium bovis BCG (Pasteur 1173P2). jMycobacterium tuberculosis H37Rv (ATCC27294). kBacillus anthracis. lP. aeruginosa. mE.
coli. nSalmonella enterica. oProteus spp. pNeisseria gonorrhoeae. qEnterobacter cloacae. rClostridium dif f icile BI/NAP1/027. sStaphylococcus epidermidis.

Salmonella typhi (MICs 0.01 μg mL−1) and P. aeruginosa (MICs
≤ 0.03 μg mL−1). Compound 72 was less active on these Gram-
negative bacteria (MICs 0.03 μg mL−1). This is the first report on
the bioactivity of 72−74, which are uncommon linear
lipopeptides that display a Leu-rich scaffold. The authors
propose biosynthetic pathways based on NRPS for the
production of gageotetrins.
In a subsequent work, the authors54 reported production by
the same strain of three new linear lipoheptapeptides,
gageostatins A−C (75−77). When tested separately, com-
pounds 75−77 inhibited both Gram-positive (S. aureus and
B. subtillis; MICs 16−32 μg mL−1) and Gram-negative bacteria
(S. typhi and P. aeruginosa; MICs 16−32 μg mL−1). However, a
synergy between 75 and 76 resulted in lower MICs for S. aureus
and P. aeruginosa (MIC 8 μg mL−1). These lipopeptides
displayed the same amino acid sequence as those of the known
1223
surfactins A−D with the difference that 75−77 are linear all-L-
Leu structures, opposed to surfactins A−D, which are L- and D-
Leu cyclic peptides. Additionally, there are new fatty acid
moieties in 76 and 77. The marked difference in antibacterial
activity between gageotetrins (72−74) and gageostatins (75−
77) may be explained by the number and composition in amino
acid residues of the peptide chain. Both features influence the
mode of action with which the chain attaches to the outer
membrane of the pathogen, eventually leading to its death.55,56
A gorgonian from the South China Sea harbored Bacillus
amyloliquefaciens SCSIO 00856, which produced a new 24-
membered-ring lactone, macrolactin V (78), and its known
epimer macrolactin S (79).57 In a dilution method assay, S. aureus
and E. coli were strongly inhibited by 78 (MICs 0.1 μg mL−1) and
by 79 (MICs ≤ 0.3 μg mL−1). B. subtilis was highly sensitive to 78
(MIC 0.1 μg mL−1), but insensitive to 79 (MIC 100 μg mL−1).
DOI: 10.1021/acs.jnatprod.6b00235
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Journal of Natural Products Review

inhibited B. subtilis and E. coli with MICs of 8 and 16 μg mL−1,

respectively. Compounds 81−84 displayed low activity or were
inactive (MICs ≥ 16 μg mL−1). Of note, the salinity of the culture
medium influenced the production of the metabolites.
Compounds 80−85 were detected at low (12 g L−1) but not at
high salinity (32 g L−1). The antibacterial activities of the new
macrolactins 80−82 were similar to those of published
macrolactins, and no major structural differences existed
among them. Comparison of the activity among the fatty acids
showed that better inhibitory properties depended on
unsaturation and the presence of hydroxy moieties (82−84)
compared to saturated fatty acids.

Structure−activity analysis revealed that the antibacterial proper-

ties of compounds 78 and 79 depended on the configuration of
the OH-7 of the epimer.
Marine Bacillus sp. 09ID19458 produced three new 24-
membered macrolactones, macrolactins X−Z (80−82), two
new hydroxy unsaturated fatty acids, linieodolides A (83) and B
(84), and known macrolactinic acid (85). Compounds 85 and 80
1224 DOI: 10.1021/acs.jnatprod.6b00235
J. Nat. Prod. 2017, 80, 1215−1228
Journal of Natural Products Review

Cultivating the B. subtilis strain 109GGC020 in culture media Table 3. Minimum Inhibition Concentration (μg mL−1) of
containing different salinities (6.0, 18.5, 25.4, and 33.0 g L−1)59 Metabolites from Bacilli
and comparing 1H NMR data from their culture extracts
S. B. P. S.
suggested that a higher number of peaks corresponding to compound aureus subtillis E. coli aeruginosa typhi ref
macrolactins can be obtained with salinity at 18.5 g L−1. This led gageotetrin A (72) 0.01 0.01 −a 0.03 0.03 53
to the isolation of three new macrolactin analogues, the gageotetrin B (73) 0.03 0.01 −a 0.03 0.01
gageomacrolactins 1−3 (86−88) and several known macro- gageotetrin C (74) 0.03 0.03 −a 0.01 0.01
lactins. The microorganism was obtained from Gageo Reef gageostatin A (75) 16 16 −a 16 16 54
sediment, Republic of Korea. Compound 86 was inhibitory gageostatin B (76) 16 32b −a 16 32b
toward Gram-positive bacteria (S. aureus, B. subtilis, and B. cereus) gageostatin A+B (75- 8 16 −a 8 32b
and Gram-negative bacteria (E. coli, S. typhi, and P. aeruginosa) 76)
with MICs in the range of 0.01−0.02 μg mL−1. Compounds 87 macrolactin V (78) 0.10 0.1 0.1 −a −a 57
and 88 were less effective, with MICs varying from 0.02 to 0.10 macrolactin S (79) 0.10 100b 0.3 −a −a
μg mL−1. Other isolated macrolactins were not tested because macrolactin X (80) −a 16 16 −a −a 58
their activities were already known. Comparing the structure− macrolactinic acid −a 8 8 −a −a
function of the new gageomacrolactins with those of known (85)
macrolactins illustrated that the antibacterial activity is not gageomacrolactin 1 0.01 0.01 0.02 0.01 0.02 59
(86)
affected by the position of the epoxide moiety. However, the
gageomacrolactin 2 0.06 0.06 0.02 0.03 0.02
bioactivity is highly dependent on the free hydroxy at C-15 of the (87)
macrolactone ring. The presence of a methoxy or ketone gageomacrolactin 3 0.06 0.06 0.06 0.03 0.03
decreased antibacterial activity. (88)
protein BL-DZ1 (89) − a
− a
− a
3.1 −a 60
a b
MIC values not available. Compound inactive against the strain
tested.

an efflux pump inhibitor, was evaluated in a mixture with several

antibiotic classes (macrolide, tetracycline, fluoroquinolones,
beta-lactam, aminoglycoside, and chloramphenicol) against
three E. coli strains overexpressing efflux pumps. The association
of 90 (2−128 μg mL−1) with the antibiotics caused a 2- to 16-fold
decrease in their MICs. In addition, 90 displayed weak
antibacterial effects on its own but with an MIC above 100 μg
mL−1. Through the metabolomic mapping of the 36 Pseudoalter-
omonas isolates screened in the study, the presence of
brominated metabolites was detected only within the P. piscicida
phylogenetic clade, the most bioactive group, suggesting a
relationship between halogenation and biosynthetic potential for
antibiotic metabolites. The paper is the first report on 90 from a
microbial source.

A protein obtained from Bacillus licheniformis D1 isolated from

a marine mussel showed antibiofilm activity.60 A hypothetical
protein (BL00275) from B. licheniformis ATCC 14580, derived
from the National Center for Biotechnology Information
(NCBI)61 database (accession number gi52082584), matched
results from the matrix-assisted laser desorption ionization time-
of-flight (MALDI-ToF) mass spectrometry analysis of the tryptic
digest fingerprint of the isolated protein, which was designated
BL-DZ1 (89). The MIC of purified 89 against P. aeruginosa and
Bacillus pumilus was 3.1 μg mL−1, whereas the MICs for
tetracycline and nalidixic acid were 40−80 and 1250−1500 μg
mL−1, respectively. The 14 kDa protein also efficiently inhibited
biofilm formation and broke up pre-established biofilms of
P. aeruginosa and biofouling bacterium B. pumilus.
Table 3 shows the antibacterial activities of the compounds
discussed in this section against several microorganisms.
Complete genome sequencing of Pseudoalteromonas sp. SANK
7339063 revealed a new 97 kb plasmid, pTML1. Two essentially
different gene clusters are embedded in the plasmid, and they
synthesize distinct compounds, pseudomonic acid A (mupir-
ocin) and pyrrothine, as well as the putative amide synthetase
responsible for linking them together. A hybrid of two known
antibiotics, the obtained mupirocin pyrrothine amide (91),
resulted from the natural joining of two separate biosynthetic
pathways. When fed mupirocin, pseudomonic acid defective
mutants were able to synthesize the hybrid compound. Both 91
and its similar compound thiomarinol A (marinolic acid
pyrrothine amide) (92) displayed antibacterial properties against
MRSA (MIC ≤ 0.03 μg mL−1) and E. coli (MIC 0.5 μg mL−1).

■ ANTIBACTERIAL METABOLITES FROM

GAMMAPROTEOBACTERIA
Mupirocin-resistant MRSA demanded higher MICs: 8 mg mL−1
with 92 and 16−32 mg mL−1 with the new compound. The
authors noted that the pyrrothine addition enhances activity of
Marine Pseudoalteromonas piscicida produced the known 3,4- pseudomonic acid A against tRNA synthase. The authors
dibromopyrrole-2,5-dione (90).62 The isolated bromopyrrole, speculate that the ability to combine separate antibiotic pathways
1225 DOI: 10.1021/acs.jnatprod.6b00235
J. Nat. Prod. 2017, 80, 1215−1228
Journal of Natural Products Review

displayed by plasmid pTML1 sets a new chapter in the

development of new derivatives of mupirocin that may be
effective against MRSA.

The surface of a soft coral from the Red Sea at Aqaba, Jordan,
provided Vibrio sp. WMBA,64 which produced seven new
maleimide derivatives: aqabamycins A−D (93−96), a mixture of
aqabamycins E (97) and E′ (98), and aqabamycins F (99) and G
(100). In a serial dilution assay, compounds 97−99 displayed the
highest activity against B. subtilis, Micrococcus luteus, E. coli, and
Proteus vulgaris, with MICs between 3 and 25 μg mL−1. The
MICs of compounds 93−96 and 100 for these bacteria varied
between 25 and >100 μg mL−1. With the exception of 93, the new molecules have been discovered with potent inhibitory
aqabamycins contain a nitro moiety. Structure−activity studies activity against current MDR pathogens. Efforts should be put
on 93 and 95 revealed the necessity of the nitro substitution for into the continuous exploration of the marine environment in the
increased antibacterial activity.

■
search for new bioactive compounds for the development of new
drugs.

■
CONCLUSION
Marine bacteria have the ability to produce metabolites of varied AUTHOR INFORMATION
chemical structures displaying antibacterial activities. These Corresponding Author
compounds present enormous potential for the discovery of new *Phone: +55 19 35212167. Fax: +55 19 35212153. E-mail:
therapeutic leads in the development of drugs with which to fight claudia_schinke@yahoo.com.br.
the current antibiotic resistance threats. During 2010−2015, ORCID
antibacterial compounds belonging to 28 diverse chemical
classes were reported, of which 10 represented a new class of
Claudia Schinke: 0000-0001-7890-1464
molecules. Over 30 new compounds were able to inhibit a variety Thamires Martins: 0000-0002-3418-902X
of bacterial strains. Macrolactins A1 and B1 (55 and 56), Sonia C. N. Queiroz: 0000-0002-1725-183X
gageotetrins A−C (72−74), and gageomacrolactins 1−3 (86− Itamar S. Melo: 0000-0003-2785-6725
88) display strong broad-spectrum activity against Gram- Felix G. R. Reyes: 0000-0003-0126-3817
negative and Gram-positive bacteria. Compounds such as Notes
anthracimycin (33) and kocurin (66) present a highly selective The authors declare no competing financial interest.
antibacterial activity against Gram-positive bacteria, and their
rescue ability in in vivo septicemia models points to possible
therapeutic leads. Besides, the efficacy of 66 is comparable to that
■ ACKNOWLEDGMENTS
The authors gratefully acknowledge the financial support
of frontline antibiotics. New mechanisms of action were also received from the Brazilian Foundation for Improvement of
detected, although not completely elucidated, in 33, in which the Higher Education (CAPES) (Grants 1267382 and 1306489) and
antibacterial effect may be due to DNA and RNA synthesis the National Council for Scientific and Technological Develop-
disruption, and in 66, which seems to be different from that of its ment (CNPq) (Grant 3053390/2013-9), Brazil.
chemical analogue thiazomycin. Molecules belonging to a new
class of antibacterial compounds, the virulence blockers, were
also reported, such as piericidin A1 (60) and the piericidin
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