COBIOT-880; NO. OF PAGES 7
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r
hMicrobially produced secondary metabolites include pep-
tides, polyketides, carbohydrates, lipids, terpenoids,
steroids and alkaloids that themselves are prepared from
primary metabolites; linking these two branches of
metabolism. The determination of the structure and
function of microbial secondary metabolites has a long
and storied history. The fact that these compounds
rise to many microbial secondary metabolites [4,5]. The
associated biosynthesis of unusual sugars, amino acids and
lipids has simultaneously been probed at the level of
mechanism and catalyst structure [6,7]. And we have also
continued to expand the analytical tools that inform on
compound structure [8]. These have been exciting and
intellectually stimulating accomplishments and while
there is much yet to uncover, the field of microbial
www.sciencedirect.com Current Opinion in Biotechnology 2011, 22:1–7An ecological perspective of mic
Jonathan O’Brien and Gerard D Wrig
Bacteria and fungi produce a remarkable array of bioactive
small molecules. Many of these have found use in medicine as
chemotherapies to treat diseases ranging from infection and
cancer to hyperlipidemia and autoimmune disorders. The
applications may or may not reflect the actual targets for these
compounds. Through careful studies of microbes, their
associated molecules and their targets, a growing
understanding of the ecology of microbial secondary
metabolism is emerging that exposes the central role of
secondary metabolites in many complex biological systems.
Address
M.G. DeGroote Institute for Infectious Disease Research and
Department of Biochemistry and Biomedical Sciences, McMaster
University, Hamilton, Ontario, L8N 3Z5, Canada
Corresponding author: Wright, Gerard D (wrightge@mcmaster.ca)
Current Opinion in Biotechnology 2011, 22:1–7
This review comes from a themed issue on
Systems biology
Edited by Roy Kishony and Vassily Hatzimanikatis
0958-1669/$ – see front matter
Published by Elsevier Ltd.
DOI 10.1016/j.copbio.2011.03.010
Introduction: Microbial natural products
The past 15 years has seen a dramatic rise in the inves-
tigation of the biosynthesis of secondary metabolites by
bacteria and fungi [1]. These natural products are differ-
entiated from the activities of primary metabolism, the
well-known anabolic and catabolic processes that that are
essential for cell growth and are highly conserved across
species, genera, and kingdoms. Secondary metabolites are
molecules of adaptation that evolved for purposes apart
from primary metabolism. In contrast to primary metab-
olites, they are produced by individual species or genera
for specific physiological, social or predatory reasons.
These compounds therefore are intimately linked with
the ecology of the producing organisms.Please cite this article in press as: O’Brien J, Wright GD. An ecological perspective of microbiaobial secondary metabolism
t
showed remarkable and varied bioactivity along with
often complex and intricate chemical structures, ensured
tremendous interest by chemists, biologists, and drug
discovers alike. The often significant challenges in puri-
fication, characterization of chemical structure and deter-
mination of biological activity prompted the development
of unique laboratory skill sets and a branch of chemistry
dedicated to natural product research and development.
Indeed, the pharmaceutical sector depended on these
molecules as sources of drugs and leads for new medicines
for the better part of the 20th Century [2]. The focus of
natural product research has therefore focused largely on
the identification of novel molecules and efforts to exploit
these as therapies for human diseases rather than the
determination of their actual function in the producing
organisms.
By the 1990s, the challenges of securing novel chemical
matter from microbial and other natural sources along
with the rise of combinatorial and related chemistries as a
more facile route to expand chemical diversity suitable for
high throughput methods in pharma, resulted in a dimin-
ished emphasis on secondary metabolites in this industry.
Indeed many pharmaceutical companies have since
closed their natural product divisions. Nevertheless, at
the same time the growing access to high throughput gene
and genome sequencing platforms and technologies has
resulted in a surge in the study of microbial natural
product biosynthesis, mostly in academe. The obser-
vation that the genetic programs for most secondary
metabolites, at least in bacteria, were clustered contigu-
ously on the chromosome, facilitated the identification of
putative biosynthetic genes [3]. The heterologous expres-
sion of these genes in tractable organisms such as Escher-
ichia coli, has enabled biochemical studies on proteins and
enzymes that otherwise would have been unachievable
using the biosynthetic proteins from natural abundance in
producing organisms.
The result has been a remarkable expansion of our un-
derstanding of how secondary metabolites are made by
microorganisms. Biochemical studies revealed the details
of the complex non-ribosomal and polyketide assembly
lines and their associated modular components that givel secondary metabolism, Curr Opin Biotechnol (2011), doi:10.1016/j.copbio.2011.03.010

2 Systems biology
COBIOT-880; NO. OF PAGES 7
c re
inasecondary metabolism biosynthesis is maturing. On the
contrary, our understanding of why microorganisms pro-
duce these remarkable compounds in the first place is
lagging. Efforts to explore the chemical ecology of
microbes are only just beginning, but the early results
are stunningly fascinating and point to an emerging era of
innovation in the determination of the chemical basis of
phenotype.
Secondary metabolites as agents of
inter-microbial warfare
Antibiotics represent some of the most successful appli-
cations of microbial natural products in human health.
The observations of pioneers such as Fleming, Dubos and
Figure 1
ATP
Vancomycin
(b)(a)
Resistance
VanR
Van
S
Van
S VanS
P
PP
+ vanXvanAvanH
Antibiotic secondary metabolites can regulate resistance. Some antibioti
example, vancomycin resistance is positively regulated by the receptor k
TetR (b).Waksman who demonstrated that environmental bacteria
and fungi produce highly specific antimicrobial secondary
metabolites ushered in the ‘Golden Age’ of antibiotics [9].
During this period, roughly between 1940 and 1960, the
majority of the antibiotic chemical scaffolds currently in
clinical use were discovered [9].
The most parsimonious explanation for why microbes
produce antibiotics is that these molecules provide pro-
ducers with a strong selective advantage in nutrient poor
environments by poisoning neighboring organisms. The
genesis of this hypothesis lies in the logic that an ability to
kill or slow the growth of competitors would favor anti-
biotic producing organisms over antibiotic susceptible
ones. In support of this hypothesis is the observation that
environmental bacteria are highly antibiotic resistant
[10,11]. Indeed antibiotic producing bacteria and non-
producers alike harbor a myriad of highly efficient anti-
biotic resistant genes. This ‘resistome’ is highly evolved,
widespread and probably ancient [12,13]. The efficiency
and specificity of many components of the resistome
argues that antibiotics are highly toxic environmental
chemicals that select for equally efficient resistance
Please cite this article in press as: O’Brien J, Wright GD. An ecological perspective of microbia
Current Opinion in Biotechnology 2011, 22:1–7mechanisms. There is now compelling evidence that
antibiotic resistance elements in the environment can
migrate into previously antibiotic sensitive pathogens,
thus the environmental resistome is a reservoir for clini-
cally relevant drug resistance [14].
The interplay between resistance and antibiotic secondary
metabolites can be quite complex. Often antibiotics induce
resistance (Figure 1). The glycopeptide antibiotics such as
vancomycin are highly important in the control of infec-
tious disease. Vancomycin resistance requires the remo-
deling of bacterial peptidoglycan [15]. This is achieved
through the action of a 3-gene operon, vanHAX, which is
regulated by a two component regulatory system, VanR
- Tet
TetR
TetR
+ Tet
+– tetAtetA
Tet Tet
Tet
Tet Tet
TetA
Current Opinion in Biotechnology
sistance mechanisms are regulated by highly specific receptors. For
se VanS (a); while the TetA efflux mechanism is negatively regulated byand VanS. VanS is a membrane bound sensor kinase that
senses vancomycin, resulting in activation of the transcrip-
tion regulator VanR and expression of vanHAX. Strepto-
myces coelicolor is a non-pathogenic soil bacterium that does
not produce vancomycin, but does have a VanR-VanS
regulated vanHAX cluster [16]. A photoaffinity label
derivative of vancomycin covalently modifies S. coelicolor
VanS demonstrating that the receptor kinase is activated by
the antibiotic [17]. The intimate link between antibiotic
and resistance in a non-producing strain is consistent with a
highly evolved protection mechanism and a role of vanco-
mycin as a toxic secondary metabolite that is produced by
other organisms as a growth inhibitor.
Another example of a chemical-genetic interaction be-
tween an antibiotic and a defense mechanism is in tetra-
cycline resistance. Resistance to tetracycline antibiotics is
very often mediated through the expression of efflux
proteins such as TetA that pump the antibiotic out of
the cell. TetA is toxic to the cell and the DNA-binding
protein TetR tightly regulates its expression. TetR is a
negative regulator of tetA expression and binds tetracycline
at low drug concentrations, whereupon it dissociates from
l secondary metabolism, Curr Opin Biotechnol (2011), doi:10.1016/j.copbio.2011.03.010
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