Abstract
BackgroundPseudomonas aeruginosa populations within the cystic fibrosis lung exhibit extensive phenotypic and genetic diversification. The resultant population diversity is thought to be crucial to the persistence of infection and may underpin the progression of disease. However, because cystic fibrosis lungs represent ecologically complex and hostile environments, the selective forces driving this diversification in vivo remain unclear. We took an experimental evolution approach to test the hypothesis that sub-inhibitory antibiotics can drive diversification of P. aeruginosa populations. Replicate populations of P. aeruginosa LESB58 were cultured for seven days in artificial sputum medium with and without sub-inhibitory concentrations of various clinically relevant antibiotics. We then characterised diversification with respect to 13 phenotypic and genotypic characteristics.ResultsWe observed that higher population diversity evolved in the presence of azithromycin, ceftazidime or colistin relative to antibiotic-free controls. Divergence occurred due to alterations in antimicrobial susceptibility profiles following exposure to azithromycin, ceftazidime and colistin. Alterations in colony morphology and pyocyanin production were observed following exposure to ceftazidime and colistin only. Diversification was not observed in the presence of meropenem.ConclusionsOur study indicates that certain antibiotics can promote population diversification when present in sub-inhibitory concentrations. Hence, the choice of antibiotic may have previously unforeseen implications for the development of P. aeruginosa infections in the lungs of cystic fibrosis patients.
Highlights
Pseudomonas aeruginosa populations within the cystic fibrosis lung exhibit extensive phenotypic and genetic diversification
Sub-inhibitory antibiotics promote diversification of P. aeruginosa LESB58 The emergence of novel haplotypes was observed in all culture conditions, but the presence of sub-inhibitory concentrations of certain antibiotics significantly increased both the number of novel haplotypes (p
There was no significant difference in the colony forming unit (CFU) values between the populations exposed to antibiotics in artificial sputum medium (ASM) and in populations exposed to ASM alone
Summary
Pseudomonas aeruginosa populations within the cystic fibrosis lung exhibit extensive phenotypic and genetic diversification. The mutations that lead to the genetic disorder cystic fibrosis (CF) predispose patients to chronic bacterial lung infections, with the opportunist Pseudomonas aeruginosa [1]. It has been argued that such diversification leads to either increased or reduced virulence [16,20] and could be crucial to understanding disease progression and treatment While all of these facets of the CF lung environment could potentially play a role in mediating the diversification of P. aeruginosa, it is not possible to disentangle or determine the relative importance of these selective forces in vivo. A powerful approach to understanding the contribution of particular selective forces to driving bacterial diversification is through experimental evolution, whereby replicate populations are exposed to defined selective conditions in the laboratory
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