Environmental bacteria as a reservoir of novel antibiotic resistance mechanisms

Streptomycetes are undisputedly the most important producers of antibiotics in the soil. Despite this, little is known about how they themselves resist antimicrobials. This is concerning as some of the most problematic resistance mechanisms we now see in the clinic have originated in the natural environment. It is therefore important to gain a better understanding of the arsenal of resistance mechanisms in the soil that have yet to be discovered.
Antimicrobial peptides (AMPs) have recently received much attention as promising new drugs. They are produced by low-GC Gram-positive firmicutes, which often share the soil habitat with streptomycetes. It is well-understood how firmicute bacteria resist AMPs, but the corresponding genes appear to be conspicuously absent from streptomycetes. Streptomyces venezuelae possesses a striking degree of resistance against AMPs. Sensitive mutants of this bacterium have been isolated, but none of the mutations are located in known antimicrobial resistance genes.
The project aims to identifying the gene(s) responsible for AMP resistance in S. venezuelae, determine how they are regulated, their wider distribution in actinomycetes, and the role of AMPs in the ecology of S. venezuelae. During the first year, this will entail selection of candidate genes responsible for AMP resistance using DNA and RNA sequencing data previously obtained from sensitive mutants by chemical mutagenesis. Candidate genes will then be transduced into sensitive mutants to identify which genes reinstate the resistant phenotype.
Once the genes responsible for resistance have been identified, further exploratory work will seek to identify the mechanism by which these genes enable resistance. This is likely to include computational modelling of the mechanism. The prevalence and relevance of the newly identified resistance mechanisms in the environment will then be investigated using genomics and community interaction approaches. Understanding the composition of identified genes in the soil community will facilitate future predictions of the potential route by which resistance genes may transfer into clinical pathogenic strains.