Exposure to phages has little impact on the evolution of bacterial antibiotic resistance on drug concentration gradients

Quan‐Guo Zhang

doi:10.1111/eva.12136

Abstract

The use of phages for treating bacterial pathogens has recently been advocated as an alternative to antibiotic therapy. Here, we test a hypothesis that bacteria treated with phages may show more limited evolution of antibiotic resistance as the fitness costs of resistance to phages may add to those of antibiotic resistance, further reducing the growth performance of antibiotic-resistant bacteria. We did this by studying the evolution of phage-exposed and phage-free Pseudomonas fluorescens cultures on concentration gradients of single drugs, including cefotaxime, chloramphenicol, and kanamycin. During drug treatment, the level of bacterial antibiotic resistance increased through time and was not affected by the phage treatment. Exposure to phages did not cause slower growth in antibiotic-resistant bacteria, although it did so in antibiotic-susceptible bacteria. We observed significant reversion of antibiotic resistance after drug use being terminated, and the rate of reversion was not affected by the phage treatment. The results suggest that the fitness costs caused by resistance to phages are unlikely to be an important constraint on the evolution of bacterial antibiotic resistance in heterogeneous drug environments. Further studies are needed for the interaction of fitness costs of antibiotic resistance with other factors.

Highlights

The worldwide spread of antibiotic resistance in bacterial pathogens has become a major public health problem
Migration of bacteria from low- to high-drug habitats can facilitate the evolution of high-level antibiotic resistance, and mutation supply may not be a crucial limiting factor for the attainable level of resistance (Baquero and Negri 1997; Couce and Blazquez 2009; Greulich et al 2012; Hermsen et al 2012)
The mutations conferring antibiotic resistance are often associated with fitness costs, in terms of reduced growth performance or competitive ability in the absence of the antibiotic to which they confer resistance; and such costs can be a constraint on the spread of resistant bacteria during drug treatment, and a driver of resistance reversion when drug use reduced (Andersson 2006; Read and Huijben 2009; Canton and Morosini 2011)

Summary

Introduction

The worldwide spread of antibiotic resistance in bacterial pathogens has become a major public health problem. It has been shown that the fitness costs of antibiotic resistance may sometimes be compensated for by additional mutations, and the antibiotic-resistant strains spread quickly during drug treatment, and often remain persistent or are only very slowly outcompeted by their susceptible relatives after drug use has been reduced (Schrag et al 1997; Levin et al 2000; Maisnier-Patin et al 2002; Gagneux et al 2006; Perron et al 2010; Andersson and Hughes 2011). Combined use of antibiotics and phages has been shown to greatly reduce the chance of resistance evolution as there is typically little cross-resistance to phages and antibiotics (Chanishvili et al 2001; Kutateladze and Adamia 2010; Zhang and Buckling 2012). Resistance to phages may impose fitness costs on the

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Conclusion