Bioorganic & Medicinal Chemistry Letters 24 (2014) 413418

Contents lists available at ScienceDirect

Bioorganic & Medicinal Chemistry Letters

journal homepage: www.elsevier.com/locate/bmcl

BMCL Digest

New natural products as new leads for antibacterial drug discovery

Dean G. Brown , Troy Lister, Tricia L. May-Dracka
AstraZeneca Pharmaceuticals, 35 Gatehouse Dr, Waltham, MA 02451, United States

a r t i c l e

i n f o

Article history:
Received 22 November 2013
Revised 13 December 2013
Accepted 14 December 2013
Available online 22 December 2013

a b s t r a c t
Natural products have been a rich source of antibacterial drugs for many decades, but investments in this
area have declined over the past two decades. The purpose of this review article is to provide a recent
survey of new natural product classes and the mechanisms by which they work.
2013 Published by Elsevier Ltd.

Keywords:
Natural products
Antibacterial
Antimicrobial

In the past decade, only seven new chemical entities (NCE) have
been approved for therapy for treatment of bacterial infections.1
The number of approvals are down substantially from the peak
years in the mid-1980s, where on average, four new drugs were
introduced to the market each year.2 The plausible reasons for this
decline are most likely a combination of factors from a changing
regulatory environment, increased drug safety standards, as well
as failure of modern drug discovery techniques, such as high
throughput screening (HTS) against the essential bacterial genome,
to deliver on the promise of large numbers of new and novel targets in antibacterial space.3,4 OShea and Moser have published
on the physical properties of approved antibacterial drugs which
stands in contrast to typical Lipinski-like molecules found in most
company screening collections (e.g., antibacterial drugs with
Gram-negative activity have log D = 2.8 vs 1.6 for non-antibacterial
drugs).5 Aside from being highly polar and zwitterionic in many
cases, many of these are also covalent inhibitors (e.g., b-lactams)
or contain other chemical features postulated to aid in outer membrane penetration of bacteria. In comparison to mammalian cells,
the cell wall of bacteria (especially Gram-negative) present a formidable barrier for traditional small molecule drug-like space
which is typically represented in corporate HTS collections. This
barrier is due to both highly polar outer membranes and prolic
efux pumps that remove foreign compounds.
Of all the drugs currently approved as antibacterial NCEs, a signicant percentage of those are either natural products themselves

Corresponding author. Tel.: +1 781 839 4101; fax: +1 781 839 4390.
E-mail address: dean.brown@astrazeneca.com (D.G. Brown).
0960-894X/$ - see front matter 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.bmcl.2013.12.059

or were derived from a natural product scaffold. Inspection of the

148 compounds utilized by OShea and Moser in their analysis
indicates that roughly 66% of these compounds fall into one of
the two natural product categories listed above. In line with the
decline in natural product NCEs seeking registration, there has also
been a steady decline in major infrastructure investments for natural product isolation amongst large pharmaceutical companies.
Up until the late 1990s and early 2000s many major pharmaceuticals companies possessed or collaborated with fully integrated natural product groups capable of large-scale fermentation, isolation,
characterization and semi-synthesis (e.g., Eli Lilly, Merck, Bayer).
Several reasons may explain why this paradigm has shifted. One
reason could be that many of the sources of soil microorganisms
capable of being cultured have already been examined and the risk
of spending signicant energy re-discovering old natural products
is too high to justify further investments. Another reason may be
the facilitation of HTS and large corporate collections which were
speculated to expedite the discovery process (e.g., HTS hits would
be more amenable to synthetic analogs in the Hit-to-lead stage).
And yet another possible reason may be a mind-set that commercial markets for novel antibacterial agents are not large and that
the pre-clinical discovery investments should be made in accordance with the predicted market and return on investment. As
such, natural products infrastructure may have been too expensive
to continue to invest in. However, the need for new antibacterial
agents remains high, with ever increasing rates of resistance of
the current drugs on the market today. If new agents are not discovered, many of the current therapies will no longer work in
the future, even for common infections.
The purpose of this review is to highlight some of the new
sources of natural products and discuss their proposed mechanisms as well as future trends. It is hoped that molecules, such

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D. G. Brown et al. / Bioorg. Med. Chem. Lett. 24 (2014) 413418

as those mentioned in this review, will spark a renewed interest in

natural products as sources for future directions in antibacterial
drug discovery. Furthermore, with signicant advances in synthetic organic chemistry (e.g., click chemistry and selective transition metal organocatalysis such as cross-metathesis, CH bond
activation), the opportunities for semi-synthesis are much greater
than those in the 19501990s and thus new advances in this area
are ripe for opportunity. Furthermore, advances in chemical biology tools and proteomics also lend themselves to the type of phenotypic screening typically done with antibacterial extracts and
may open up new areas previously undiscovered.
Secretory pathways: Signal peptidase I and II inhibitors. The secretory pathway in bacteria is responsible for translocation of
pre-proteins from the cytoplasm for assembly into cell-wall structures.6 These pre-proteins contain signal peptides which are
cleaved off by bacterial enzymes called signal peptidases.7 An
attractive feature of this pathway is that it is located in the periplasmic space of the Gram-negative cell wall envelope, and as such,
drug molecules need only to penetrate the outer membrane of
Gram-negative bacteria to engage the target. Inhibition of this
pathway is proposed to lead to cell death by accumulation of
pre-proteins. Two targets for which natural product inhibitors have
recently been reported are type 1 signal peptidase (SPase I: membrane-bound serine protease with a Lys-Ser catalytic dyad) and
type II signal peptidase (SPase II: membrane-bound aspartyl
protease)7
The arylomycins (1, Fig. 1) were identied from a strain of Streptomyces and are lipohexapeptides which were found to inhibit bacterial SPase I.8,9 These compounds have activity against wild-type
Staphylococcus epidermis, (MIC = 0.25 lg/mL) but do not have

signicant activity in wild-type Staphylococcus aureus, Escherichia

coli or Pseudomonas aeruginosa. It was demonstrated that these latter three organisms have a proline residue in the active site rather
than a serine in the case of S. epidermis.10 This change no longer
accommodates an important H-bond to the peptidic side chain of
arylomycin. Activity was regained in the proline to serine mutants
of these bacteria (S. aureus MIC = 2 lg/mL, E. coli MIC = 4 lg/mL
and P. aeruginosa MIC = 8 lg/mL) and conversely lost in S. epidermis
by mutating from serine to proline (S. epidemeris S29P MIC = 8 lg/
mL, a 32-fold loss). Binding data in E. coli is consistent with this
hypothesis, where 1 has a KD for E. coli Spase I of 979 69 nM for
the proline wild-type species as compared to 39 15 nM for the
serine mutant (P84S).10 The arylomycins also exist in glycosylated
forms, which does not appear to interfere with antibacterial activity and may instead offer solubilizing properties.11 The arylomycins have also been shown to synergize when co-administered
with aminoglycosides, but not with other classes of antibiotics.12
Two other molecules have been identied recently as inhibitors
of SPase 1 from Staphylococcus (SPase termed SpsB).13 Actinocarbasin (2) is related to arylomycin, but is polysulfated, glycosylated
and has different side-chains extending from the macrocycle than
that of arylomycin. This compound has an MIC range from 0.5 to
128 lg/mL against 10 isolates of methicillin-resistant Staphylococcus aureus (MRSA). Krisynomycin (3) is a cyclic depsipeptide with
antimicrobial activity against clinical isolates of MRSA (MIC range
from 16 to 128 lg/mL against 24 clinical isolates). Of note is the
fact that they both potentiate the activity of the b-lactam antibiotic
imipenem, with restoration of imipenem potency against MRSA at
concentrations 16-fold below their MIC. These compounds do not
appear to synergize with other classes of antibiotics an interesting

Me
HO
HO

OH
O

HO
OH
HO 3SO

Me

Me

Me
N

( )13

Me

N
H
OH

H
N

O
N
Me

H
N
O

CO2 H

( )7

Me

NH

O
Me

Me

Me

H
N

HN

H
N

N
Me

O
HO3 S

Me

1, Arylomycin A-C 16

CO2 H
NH

Me

2, Actinocarbasin

CO2H

O
Me

SO 3H
O

NH
SO3 H

O
O O

HN
i-Pr

N
H

HN
O

HO
NH
O

Me
H
N

N
OO
O

Me

NH
H
N

( )n
O
O

NH

NH

i-Pr

Cl

i-Pr

Me Me
O
N

HN
H
N

Cl

O
HO

25
O
NH

O
Et

O Me
NH
OH

H
HN
Me

i-Pr

Me

Me

HN

OMe
OH

14

OH
Me

OH

Me
Me

3, Krisynomycin

4, n = 4, Globomycin
5, n = 8

6, Myxovirescin A1, C-14 C=C, C-25 = (R)

7, Myxovirescin A2, C-14 C=C, C-25 = (S)
8, Dihydromyxovirescin = C-14 CC, C-25 = (R)

Figure 1. Type 1 signal peptidase inhibitors arylomycin 1, actinocarbasin 2, & krisynomycin 3. type II signal peptidase inhibitors globomycin 4 and 5 and myxovirescin
scaffolds 6, 7, 8.

D. G. Brown et al. / Bioorg. Med. Chem. Lett. 24 (2014) 413418

contrast to arylomycin mentioned above. It is proposed that the

potentiating effect is due to prevention of signal-peptidase mediated secretion of necessary proteins utilized in b-lactam resistance
pathways.
Two natural product lead structures have been identied which
engage SPase II: (a) globomycins 4 & 51416 and (b) myxovirescins
6, 7, 8 (or antibiotic TA, produced by myxobacteria).17 Of interest is
that these two distinct classes of macrocyles (cyclic peptide and
polyketide) inhibit the same target. Although this target is an
aspartyl protease, neither structure is reminiscent of any
traditional aspartyl protease inhibitor from other therapy areas
(e.g., HIV protease, renin, b-secretase). Both chemotypes possess
activity against E. coli (4, E. coli SANK70569 MIC = 12.5 lg/mL; 5,
E. coli SANK70569 MIC = 1.56 lg/mL; 6, NCTC10418 E. coli
MIC = 6.25 lg/mL; 8 E. coli NCTC10418 MIC = 3.12 lg/mL).18,19 It
is interesting that the increase in the size of the lipophilic tail for
globomycin increases activity by roughly 10-fold (4 to 5). This
raises an interesting question on how these molecules penetrate
the polar lipopolysacchride outer membrane of E. coli given their
size, and if an increase in lipohpilic size enables penetration for
these macrocyles. It is possible that an unknown active transport
mechanism enables the bacterial penetration, but this has not been
reported to date in the literature. A solid phase synthesis of globomycin has been reported which has provided analogs as well as
some SAR development.20 Syntheses and stereochemical assignment of myxovirescin A1 is also known.19,21
Protein synthesis inhibitors Inhibitors of protein synthesis
encompass several important classes of therapeutically useful antibiotics. For example, tetracyclins, macrolides, and aminoglycosides
are all classied as protein synthesis inhibitors which disrupt the
function of the 70S ribosome at varying stages thereby halting protein synthesis. The ribosome is a multimolecular complex, composed of a small (30S) and large (50S) subunit; it is functionally
diverse which allows for many opportunities for the disruption of
mRNA translation into proteins (initiation, aminoacyl tRNA entry,
proofreading, peptidyl transfer, ribosomal translocation, and termination).22 Although this is a rich target class of antibacterial
agents, resistance and undesirable side effects have led to a continual search for new inhibitors with novel mechanisms of action. Of
signicance in the eld is the determination of high resolution Xray crystal structures of the ribosome. In 2000 the crystal structure
of the 50S from Haloarcula marismortui (2.4 )23a and 30S from
Thermus thermophilus (3 )23b were solved, and in 2005 the 30S
of the more relevant pathogen E. coli (3.5 )23c was solved. This
has been a technically very challenging area compared to enzyme
structural biology, but these continual advances in ribosome structural biology will most certainly enable this eld for more routine
structure based drug design.
A recent high throughput screen of 6700 microbial extracts led
to the identication of orthoformimycin (9).24 Isolated from Streptomyces griseus, orthoformimycin contains a novel orthoformate
ester, a functional group that had previously only been observed
in fungal and bacterial secondary metabolites. Orthoformimycin
exhibits moderate-to-poor antibacterial activity against several
organisms, including Bacillus subtilis (MIC = 70 lg/mL). Although
further investigations are needed to fully elucidate its mechanism
of action, initial data indicates a novel 50S binding mode that
inhibits translational elongation.
Another promising protein synthesis inhibitor is bottromycin A
(10) and analogs thereof. Although this natural product was rst
isolated in 1957, its absolute conguration was only recently conrmed through an enantioselective total synthesis.25 Bottromycin
shows potent activity against MRSA and vancomycin-resistant
Enterococci (VRE) (MICs = 1.0 and 0.5 lg/mL, respectively).26 Along
with recent synthetic progress on bottromycin, the gene cluster
responsible for biosynthesis has also been indentied.27 This

415

antibacterial activity is the consequence of a unique mechanism

of action that involves blocking aminoacyl tRNA from connecting
to the A site on the 50S ribosome. Despite compelling in vitro
activity, bottromycin faces signicant challenges for its use as a
therapeutic as in vivo studies have shown rapid methyl ester
hydrolysis in plasma (R-group of 10 in Fig. 2), with the resulting
carboxylic acid metabolite exhibiting attenuated activity (MRSA
MIC = 64 lg/mL). A recent publication, however, has demonstrated
that replacing the methyl ester with a propyl ketone (11) retains
activity against drug resistant organisms and shows improved
plasma stability.26
Antimicrobial peptides Antimicrobial peptides (AMPs) have
long been recognized as Natures defence against invasive bacterial
infection.28 Perhaps better categorized as host-defense peptides,
they elicit the ability to modulate immune response through various mechanisms to complement intrinsic, although often weak
(in vivo), antimicrobial activity. AMPs are synthesized at the ribosome as a gene-encoded precursor peptide followed by post-translational proteolytic activation. Highly diverse, AMPs are broadly
categorized based on their secondary structure, which is amphipathic in design due to spatially organized clusters of hydrophobicity and cationic character. More specically, AMPs are between
1050 amino acids, positively charged (between+2 and +9) and
comprised of P30% hydrophobic residues. These structural features underpin the typically accepted mode of action of these molecules, which is binding to and disruption of the microbes (and
host) cell membrane, although additional mechanisms may be at
play. AMPs have not fared well as therapeutics due to a combination of poor in vivo activity, extensive proteolysis, high manufacturing costs, and unmanageable safety margins. Modication of
these natural products is proving increasingly successful at overcoming many of the short-falls hindering use as therapeutics.
A recent example from Polyphor AG describes the chemical evolution of protegrin 1 (PG-1) to POL7080 (structure unknown), a
candidate for serious Pseudomonas aeruginosa infections that has
recently successfully completed phase 1 trials.29 PG-1 was identied from porcine leukocytes as an antimicrobial with moderate
activity against Gram-positive and Gram-negative bacteria, fungi
and some enveloped viruses. With a mechanism consistent with
membrane disruption via pore formation, PG-1 also exhibited signicant hemolysis and, as such, had limited clinical use. PG-1 contains 18 amino acids and is ordered into an anti-parallel b-strand
by two disulde bridges. Polyphor AG developed a D-prolineL-proline template grafted into a peptidomimetic scaffold to simulate
and stabilize the b-hairpin conformation exhibited by PG-1. From
this concept they generated a diverse library of peptidomimetic
macrocycles. One sequence variant in this library (L8-1) exhibited
broad spectrum antibacterial activity with reduced hemolysis.
Iterative rounds of synthesis generated analogues with an increasingly potent and selective prole (L19-45, L26-19, L27-11 (12),
POL7001), ultimately producing POL7080, a PG-1 peptidomemetic
with P. aeruginosa (ATCC 27853) MIC of 0.008 lg/mL and ED50 of
0.250.55 mg/kg in a mouse septicaemia model. POL7080 is inactive
against other Gram-negative and Gram-positive bacteria, is
non-hemolyic at 100 lg/mL and has high plasma stability across
species. Utilizing various chemo-proteomic and genetic techniques, Polyphor AG established that progenors of POL7080 (and
thus by extrapolation, POL7080 itself) exhibit antibacterial activity
by disrupting the LPS trafcking pathway in P. aeruginosa through
binding the essential outer membrane protein, LptD. Seemingly
justifying the considerable excitement generated by the discovery
of POL7080, Roche recently announced a licensing agreement with
Polyphor AG for upto $547 M to co-develop POL7080.
A distinct, yet equally diverse group of AMPs are alternatively
produced in microbes by non-ribosomal-peptide synthetases.
Exhibiting intrinsic, potent antibacterial activity, polymyxin B,

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Me

Me
N

Me

Me
O
O

O
HO
OH

t -Bu
N
H

i-Pr

OH

HN

HN

OH

O
HO

9, Orthoformimycin

Me
O

Me
Me
N
H
N
O

H H
N

N
H

N
R

O
O

t-Bu

10, Bottromycin A, R = OMe

11, R = Propyl

Figure 2. Protein synthesis inhibitors orthoformimycin and bottromycin.

R
R

F12
R9

V14

Y7

V16

L5

R18

G3

NH2

G2

R1

Protegrin I

NH

NH 2
HN

HN

NH
O
N
H

H
N

N
H

O
H
N
O

N
H
Me

NH
NH2

NH2

DP
LP

NH2

12

11

Peptidomimetics

NH
H 2N

10

O
N
H

Me
O

O 3
H
N
O

N
H

O
H
N

N
H
Me

O
OH
1

Me
NH 2

12

H
N

NH

NH 2

12, L27-11

Position
Compound

10

11

12

L8-1

L19-45

L26-19

L27-11

POL7001

Figure 3. Peptidomemetic macrocycles.

vancomycin, and daptomycin are scarce examples of unadulterated natural product AMPs that have successfully passed clinical
trials and have been commercialized. Although safety remains an
issue with these agents, their potent, broad spectrum activity
and marginal pharmaceutical properties endears them with last
line of defence status for highly drug resistant bacteria (Fig. 3).
Topoisomerase inhibitors Type II topoisomerase is a clinically
validated antibacterial drug target and inhibition blocks DNA synthesis. At least two pathways involving this protein are known;
namely, disrupting the topoisomerase-DNA complex (so-called
topoisomerase poisons) and/or interrupting catalytic turnover

(topoisomerase inhibitors).30 Fluoroquinolones, for example, are

considered topoisomerase poisons. In 2011, Merck disclosed a novel natural product, kibdelomycin (13), that was isolated from S.
aureus collected from a soil sample from the Central Africa Republic.31 Kibdelomycin is a relatively complex natural product comprised of ve distinct structural subunits: a tetramic acid
bridging a novel sugar residue through a N-glycosidic linkage and
to a decalin subunit through an enol linkage. The decalin is in turn
connected to a hexopyranose by an O-glyosidic bond and the hexapyranose is capped via a 3,4-dichloro-pyrrolamide. The natural
product exhibits potent whole cell activity against wild-type

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D. G. Brown et al. / Bioorg. Med. Chem. Lett. 24 (2014) 413418

Gram-positive bacteria (MIC = 2.0 and 0.5 lg/mL for S. aureus and
MRSA, respectively). Moderate levels of inhibition were also
observed in a TolC efux pump mutant of E. coli (MIC = 32 lg/
mL), but no activity against wild type Gram-negative pathogens
was evident (E. coli MIC >64 lg/mL), likely due to poor permeability and/or efux. The activity associated with kibdelomycin is
similar to that observed in the structurally unrelated natural products, novobiocin (14) and clorobiocin (15).32 The mechanism of
action is hypothesized to involve inhibition of the ATPase activity
of type II DNA topoisomerases, which leads to obstruction of
DNA synthesis and cell death.
Independently, researchers at AstraZeneca discovered pyrrolamide 16 through a fragment-based lead generation approach
(FBLG).33 X-ray co-crystallography of early pyrrole containing hits
from the FBLG in the S. aureus GyrB N-terminal ATP binding
domain showed a hydrogen bond between the pyrrole-NH and
aspartic acid-81. In an effort to improve potency of these early hits,
a 3,4-dichloro substituent was installed on the pyrrole to increase
hydrophobic interactions in the adenine pocket and to reduce the
pKa of the NH group to make it a better hydrogen bond donor. This
modication lead to >150 fold increase in potency over the initial
hit. Pyrrolamide 16 exhibits single digit micromolar MIC activity
across a range of Gram-positive bacteria. This represents an interesting example whereby the properties of a fully synthetic DNA
gyrase inhibitor drug candidate were altered by the incorporation
of a functional group (3,4-dichloropyrrole amide) that was subsequently identied as a component of a natural product that exhibits the same mode of action; thus medicinal chemistry mimicking
nature in parallel discovery pathways (Fig. 4).
Emerging classes of new natural product space Despite the decline in research dedicated to natural products discovery and
development, natural products with compelling biological proles
and new structural diversity continue to be discovered as exemplied by the following two recent examples (Fig. 5).
In 2011, Rene De Mot and co-workers at the Katholieke Universiteit Leuven disclosed a new amphipathic salicylate containing
antibiotic, promysalin (17).34 Promysalin is uniquely comprised of
a 2-pyrroline carboxylate that bridges a single salicylic acid moiety
and a 2,8-dihydroxymyristamide side chain. These three distinct
structural features are derived from three different central metabolites that are elaborated and combined by a previously unknown

gene cluster combination. Produced by Pseudomonas putida, promysalin facilitates swarming characteristics and biolm formation in
the producing strain, but is antagonistic to other Pseudomonads
including MDR clinical isolates of P. aeruginosa (IC50 = 0.16 lg/mL
and minimum bactericidal activity (MBC) = 100 lg/mL against
PA14). Indeed, of the 16 Pseudomonas species tested, 12 had sensitive strains, and in a broader panel of P. aeruginosa environmental
and clinical isolates, all 83 were sensitive. This intriguing microbiological prole warrants further investigation, and additional work
is required to elucidate the absolute stereochemistry, mechanism of
action and structure activity relationships of promysalin.
At the 53rd ICAAC meeting (Denver, Colorado 2013) a group of
researchers from Fundacion Medina, Cubist Pharmaceuticals and
the University of California, San Diego presented a poster
disclosing a family of novel natural product antibiotics (MDN
005760).35 Isolated from the crude fermentation extract of a lamentous fungus, these natural products possess two isonitrile
functional groups, which although rarely found in natural products, are not unprecedented. Indeed, MK4588, an antibiotic natural
product isolated from Leptospaeria fungus by Gomi and co-workers
in 1990, would appear to be related.36 MDN-0057 exhibits potent
broad spectrum Gram-negative activity with MIC ranging
0.2564 lg/mL against E. coli, Acinetobacter baumannii, P. aeruginosa
and K. pneumonia clinical isolates. MIC values are signicantly lower in efux pump mutant or permeabalized strains of these organisms indicating a propensity for efux and poor permeability for
this chemotype. MDN-0057 did not inhibit S. aureus (>128 lg/
mL) or eukaryotic cell growth (HepG2 and Fa2N4 >512 lg/mL)
and was inactive in the hERG K channel at 50 lM. A study of the
impact of MDN-0057 on macromolecular synthesis indicated a
concentration dependant inhibition of cell wall synthesis, but not
RNA, DNA, protein or lipid synthesis. Additionally, cytology experiments showed that incubation of E. coli cells with MDN-0057 rendered the cells more permeable to DAPI and sytox green (dyes)
thus reinforcing a cell wall target related mode of action.
In summary, natural product research continues to be an important cornerstone for antibacterial drug discovery. With modern advances in selective organic synthesis, ribosome crystallography,
chemical biology tools for target elucidation, and novel methods
for uncovering new natural products, this area can continue to
provide new medicines towards unmet patient needs.

O
O

NH2

Me

O
O

HO
H

Me
i-Pr

Me

Me

Me

HO

HO
O

O
Me

Me

O Me

HN

O
O
HN
O
Me

HO

Me

OH

OH

HO
Me

NH

HO
O

Cl

H 2N
Cl

O
HN

O
Me

S
N

O
OH

O
Cl

Me
Me

Me

H
N

HO
O

O
Me

Me
Me

NH
Cl

O
HN

Cl
Me

Me

13, Kibdelomycin

14, Novobiocin

15, Clorobiocin

16, AstraZeneca FBLG effort

Figure 4. Topoisomerase inhibitors from natural sources (13, 14, and 15) and synthetic preparation (16).

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D. G. Brown et al. / Bioorg. Med. Chem. Lett. 24 (2014) 413418

R
O

OH

N
O

R
O

Me

O
HO

N C
C

HO

N C

OH
H

N C
N

OH
O

17, Promysalin

NH2

OMe

OMe

18, MDN-0057, R = OH
19, MDN-0059, R = H

OMe

20, MDN-0058, R = OH 22, MK4588

21, MDN-0060, R = H

Figure 5. New natural product space.

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