Abstract
The rapid rise of antibiotic resistance has renewed interest in phage therapy – the use of bacteria‐specific viruses (phages) to treat bacterial infections. Even though phages are often pathogen‐specific, little is known about the efficiency and eco‐evolutionary outcomes of phage therapy in polymicrobial infections. We studied this experimentally by exposing both quorum‐sensing (QS) signalling PAO1 and QS‐deficient lasR Pseudomonas aeruginosa genotypes (differing in their ability to signal intraspecifically) to lytic PT7 phage in the presence and absence of two bacterial competitors: Staphylococcus aureus and Stenotrophomonas maltophilia–two bacteria commonly associated with P. aeruginosa in polymicrobial cystic fibrosis lung infections. Both the P. aeruginosa genotype and the presence of competitors had profound effects on bacteria and phage densities and bacterial resistance evolution. In general, competition reduced the P. aeruginosa frequencies leading to a lower rate of resistance evolution. This effect was clearer with QS signalling PAO1 strain due to lower bacteria and phage densities and relatively larger pleiotropic growth cost imposed by both phages and competitors. Unexpectedly, phage selection decreased the total bacterial densities in the QS‐deficient lasR pathogen communities, while an increase was observed in the QS signalling PAO1 pathogen communities. Together these results suggest that bacterial competition can shape the eco‐evolutionary outcomes of phage therapy.
Highlights
Growing concern for the evolution of antibiotic resistant bacteria and in particular for multiresistant gram-negative bacteria (Levy & Marshall, 2004), has led to renewed interest in alternative treatments including phage therapy (Rossolini, Arena, Pecile, & Pollini, 2014)
We hypothesized that the rate of phage resistance evolution could be negatively affected by competition via negative effects on population densities and that the effect of competition could further depend on the focal pathogen genotype, the composition of competitor community and the pleiotropic costs of adaptation
We studied the role of bacterial competition for the efficiency and eco-evolutionary outcomes of phage therapy in model polymicrobial infections in vitro
Summary
Growing concern for the evolution of antibiotic resistant bacteria and in particular for multiresistant gram-negative bacteria (Levy & Marshall, 2004), has led to renewed interest in alternative treatments including phage therapy (Rossolini, Arena, Pecile, & Pollini, 2014). There might be trade-offs between evolving phage resistance and retaining competitive ability or virulence due to conflicting selection pressures (Friman & Buckling, 2014) Such trade-offs are often manifested as antagonistic pleiotropy where a mutation in the gene that confers benefit in the presence of phage has a negative effect on some other function such as uptake of nutrients (Lenski & Levin, 1985). We used in vitro experimental evolution approach to study the eco-evolutionary outcomes of phage therapy with P. aeruginosa focal pathogen that frequently co-infects the lungs of patients with CF (Harrison, 2007) We manipulated both the presence of Staphylococcus aureus and Stenotrophomonas maltophilia competitors (one or two competitors present–our definition of a polymicrobial community from here on) and the PT7 phage and used two P. aeruginosa pathogen genotypes: QS signalling PAO1 strain and QS-deficient lasR mutant strain, which does not produce or respond to QS signals We hypothesized that the rate of phage resistance evolution could be negatively affected by competition via negative effects on population densities (lowered mutation supply rate and phage–bacteria encounter rates) and that the effect of competition could further depend on the focal pathogen genotype, the composition of competitor community and the pleiotropic costs of adaptation
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