Abstract
BackgroundFitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. The scale of these costs is highly variable. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. However, this is not supported by surveillance data in healthy communities, which indicate that this resistance mechanism is relatively unsuccessful.ResultsEpistasis analysis on two collections of MRSA provides an explanation for this discord, where the mupirocin resistance-conferring mutation of the ileS gene appears to affect the levels of toxins produced by S. aureus when combined with specific polymorphisms at other loci. Proteomic analysis demonstrates that the activity of the secretory apparatus of the PSM family of toxins is affected by mupirocin resistance. As an energetically costly activity, this reduction in toxicity masks the fitness costs associated with this resistance mutation, a cost that becomes apparent when toxin production becomes necessary. This hidden fitness cost provides a likely explanation for why this mupirocin-resistance mechanism is not more prevalent, given the widespread use of this antibiotic.ConclusionsWith dwindling pools of antibiotics available for use, information on the fitness consequences of the acquisition of resistance may need to be considered when designing antibiotic prescribing policies. However, this study suggests there are levels of depth that we do not understand, and that holistic, surveillance and functional genomics approaches are required to gain this crucial information.
Highlights
Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination
Validation of the epistatic association between mupirocin resistance and toxicity We have previously identified toxicity-associated, epistatic interactions occurring between the mupirocin resistance-conferring SNP in the ileS gene (G1762 T, which confers the V588F change in the protein) and other polymorphic loci within a collection of ST239 methicillin-resistant S. aureus (MRSA) isolates [22]
The epistasis test within the whole genome association analysis toolset PLINK [24] compares the toxicity of isolates with each allele of a specific locus in combination with each allele identified at all other loci within the collection, i.e. it tests whether the co-occurrence of SNPs in any two loci is significantly associated with a phenotype
Summary
Fitness costs imposed on bacteria by antibiotic resistance mechanisms are believed to hamper their dissemination. Some, including resistance of Staphylococcus aureus to the clinically important antibiotic mupirocin, have been reported as being cost-free, which suggests that there are few barriers preventing their global spread. As antibiotics are most commonly used for short and defined periods of time, resistant bacteria are under selection to reduce these costs to avoid displacement once treatment has finished In many cases this is achieved through compensatory mutations that allow many resistance mechanisms to be stably maintained in Staphylococcus aureus is an example of a major human pathogen [8] that has become more challenging to treat due to the emergence of antibiotic resistance, with methicillin-resistant S. aureus (MRSA) being the most notable example [9]. Such decolonisation has been reported to reduce S. aureus infections of post-surgical wounds by 58%, of haemodialysis patients by 80% and of peritoneal dialysis patients by 63% [14]
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