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What are metabolites?

Microorganisms live in a world of chemical signals. They use small molecular weight compounds (<2,500 amu), known as metabolites, to regulate their own growth and development, to encourage other organisms beneficial to them and suppress organisms that are harmful. To control competitors, microbes produce antibiotics, such as penicillin, streptomycin and erythromycin, antifungals, such as nystatin, amphotericin and cycloheximide, antiprotozoan metabolites including monensin, salinomycin and trichostatins and herbicides like herbicidin and bialophos.  To reduce predation by larger organisms they produce nematocides, such as the avermectins and paraherquamide, and insecticides such as the milbemycins, piericidins and spinosads. To encourage plants and animals they produce growth stimulants and metabolites that inhibit pathogens.

Many microbial metabolites are exquisitely selective, others are broadly active against many species. Organisms resilient or resistant to the effects of metabolites thrive; sensitive organisms falter.  Microbes use metabolites to regulate the environment in which they live and from this platform they control the function and shape of much of the world’s biodiversity.

Microbial metabolites represent an incredibly diverse array of chemistry. Microbes can make molecules that synthetic chemists cannot access. While over 25,000 microbial metabolites have been reported in the scientific literature, fewer than 2% of these have ever been readily available to the wider research community.  Most metabolites have only ever existed in small quantities in the research laboratory in which they were discovered and their biological activity has never been fully investigated.

Metabolites and human health

In the space of 60 years, man has learnt to harness the chemical diversity available from microbes for the benefit of human health.  The fungal metabolite, penicillin, heralded the beginning of the golden age of antibiotics with hundreds of microbial metabolites investigated as agents for the control of bacterial diseases.  Treatments for fungal infections, parasitic infestations and a range of cancers followed.

Today microbial metabolites are also used for therapeutic applications that move beyond controlling infections. Sophisticated enzyme and receptor bioassays have identified new metabolites that act to regulate rather than kill.  The antifungal metabolite, compactin, selectively inhibits 3-hydroxy-3-methylglutaryl-CoA reductase, an enzyme in the pathway for sterol synthesis.  The discovery of this activity led to the development of a whole new class of drugs, the statins, as lipid lowering reagents in humans. Understanding the biology of organ rejection has led to the discovery of immunosuppressants such as rapamycin, tacrolimus and cyclosporin, among others.

The chemical diversity present in the thousands of metabolites produced by microorganisms remains an unparalleled resource for the discovery of new pharmaceuticals for human and animal health.

Metabolites as probes to understand life at the molecular level

Microbes tailor metabolites to manipulate cellular processes and pathways. Scientists are becoming increasingly aware of the potential for using microbial metabolites as molecular "bioprobes" to investigate processes and pathways at the cellular level and unlock the secrets of how cells work. While genomics, proteomics and other molecular approaches provide our current view of the cell’s "hardware", it is the use of microbial metabolites as bioprobes that is helping to decode the complex “software” of functioning cells.

Antimicrobial metabolites like bafilomycin, fostriecin, geldanamycin, herbimycin, leptomycin and tautomycin have all found important roles as bioprobes in cell biology.  Likewise many mycotoxins, first recognised as livestock poisons and hazards to human health, have been re-discovered as important molecular reagents.  These include the aflatoxins, cytochalasins, tentoxin, fumitremorgin C and fumonisins. 

There have been few enzymes and receptors studied for which microbial metabolite antagonists or agonists have not been found.  This reflects the key role of metabolites in nature.  As a microbe’s success relies on its ability to control its environment, so cellular events essential to one organism will become targets for another organism to modulate in its favour.  This competitive interplay at the microbial level has been exploited by researchers to understand life at the molecular level.

Analogues

Microbes often produce not just one member of a metabolite class but a complex mixture of analogues, metabolites with closely related chemical structures. 

The bafilomycins provide an interesting example. A typical bafilomycin producing Streptomyces will yield a range of analogues: bafilomycins A1, B1, C1 and D, with A1, B1 and C1 able to be converted non-enzymatically to A2, B2 and C2.  Why does the microorganism expend the energy to produce so many closely related chemicals?  Why make metabolites which are readily modified by non-enzymatic means to provide further structural diversity? Does this production of multiple analogues reflect a redundancy in nature?  Or does the presence of so many analogues serve a purpose? 

Bafilomycins are active against bacteria, fungi, insects, nematodes and mammalian cells, but the potency of these activities varies from analogue to analogue, with each having a distinct pattern of selectivity for these targets. Microbes have learnt that there can be subtle variations in the structures of the receptors with which their metabolites interact.  By providing a range of analogues bafilomycin producers appear to be ensuring a broad inhibition across a range of variations or 'sub-types' in the bafilomycin receptor site, the significance of which we are yet to grasp.

LD50 values (ug/ml) for Bafilomycin analogues against a range of targets

Nematodes

 

Bacteria

 

  Fungi

     

Analogue

Haemonchus

 

E. coli

Bacillus

 

Saccharomyces

Septoria

Botrytis

Phytophthora

 A1

3.1

 

NI*

NI

 

NI

6.3

0.20

NI

 B1

3.1

 

NI

25

 

100

NI

1.6

100

 B2

0.39

 

NI

25

 

6.2

NI

12

12

 C1

13

 

NI

NI

 

6.3

100

1.6

25

 C2

3.1

 

NI

100

 

0.39

3.1

12

0.20

 D

13

 

NI

NI

 

50

NI

6.3

NI

* No activity

Exploring structure-activity relationships, the way in which a biological activity varies with subtle differences in the structure of an inhibitor, provides the most readily accessible route to understanding micro-diversity within receptor function. Microbes often provide us with a ready supply of related structures but most of the analogues reported are largely ignored, while research focuses on just a single analogue.  The availability of analogues of known actives offers considerable potential to help characterise selectivity within receptor sub-types. Yet, until now, access to many of these metabolites has been non-existent.

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