Mining Genomes for Antimicrobials

searching for new antibioticsWhile looking through some “Top Ten” lists of the various science stories and discoveries of 2014, I came across a paper, published in Cell in September, describing a new approach to the search for antimicrobials. The paper’s authors screened the vast amount of genomic data from the human microbiome project against known sequences to find genes with homology to existing small molecule drug candidates.

The authors reasoned that any genes that were common across many species would be more likely to affect conserved microbe:host or microbe:microbe interactions. Having identified a large group of these gene clusters, they then homed in on a subset that was commonly found in the microbiome of healthy individuals. As a proof-of-concept, they then identified and characterized a thiopeptide molecule produced by the bacterium Lactobacillus gasseri  and showed that it had the expected antimicrobial activity. The Cell paper was the first report of the characterization of any small molecule drug candidate isolated from the human microbiome.

What’s a Thiopeptide?

Thiopeptides are a relatively new class of antibiotic that are of interest because they show potent activity against various drug-resistant Gram-positive pathogens, including  methicillin-resistant Staphylococcus aureus (MRSA),and one candidate thiopeptide is currently under trial for treatment of Clostridium difficile infections. The new thiopeptide discovered in the microbiome and characterized in the Cell study,  “Lactocillin”, was similar in activity to others of the same antibiotic class, having activity against Gram-positive, but not Gram-negative, organisms (including Staph. aureus).

Why Does this Matter?

In their discussion, the authors point out the significance of these findings as follows:

…small-molecule products of biostythetic gene clusters are widely used in the clinic, and they constitute much of the chemical language of interspecies interactions. Our data highlight the fact that there exist hundreds of widely distributed BGCs of unknown function in the human microbiome, and they provide a template for future experimental efforts to discover biologically active small molecules

As I mentioned at the start of this post, this story made it into at least one year-end listing of significant findings about microbes in 2014: “9 Amazing and Gross things Scientists Discovered about Microbes this Year”. There was a lot of news about the microbiome in 2014, and much discussion on the significance of some of the correlations reported between our various bacterial colonizers and our health. The Cell paper details one application of microbiome studies with an immediate and practical use. This particular study showed how, if you know what you are looking for, the microbiome data can be a rich source of potentially useful related compounds. By implication, the microbiome could also be a source of many compounds that are new to science—if we could find the right keys to identify them.

Here’s the paper:

ResearchBlogging.orgDonia MS, Cimermancic P, Schulze CJ, Wieland Brown LC, Martin J, Mitreva M, Clardy J, Linington RG, & Fischbach MA (2014). A systematic analysis of biosynthetic gene clusters in the human microbiome reveals a common family of antibiotics. Cell, 158 (6), 1402-14 PMID: 25215495

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Isobel Maciver

Isobel is a graduate of the University of Edinburgh and of Aston University in Birmingham, U.K. She is a technical writer and editor, and is also manager of the Scientific Communications group at Promega. She enjoys writing about issues in science and communication.

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