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Abstract
Antibiotic resistance has wide-ranging effects on bacterial phenotypes and evolution. However, the influence of antibiotic resistance on bacterial responses to parasitic viruses remains unclear, despite the ubiquity of such viruses in nature and current interest in therapeutic applications. We experimentally investigated this by exposing various Escherichia coli genotypes, including eight antibiotic-resistant genotypes and a mutator, to different viruses (lytic bacteriophages). Across 960 populations, we measured changes in population density and sensitivity to viruses, and tested whether variation among bacterial genotypes was explained by their relative growth in the absence of parasites, or mutation rate towards phage resistance measured by fluctuation tests for each phage. We found that antibiotic resistance had relatively weak effects on adaptation to phages, although some antibiotic-resistance alleles impeded the evolution of resistance to phages via growth costs. By contrast, a mutator allele, often found in antibiotic-resistant lineages in pathogenic populations, had a relatively large positive effect on phage-resistance evolution and population density under parasitism. This suggests costs of antibiotic resistance may modify the outcome of phage therapy against pathogenic populations previously exposed to antibiotics, but the effects of any co-occurring mutator alleles are likely to be stronger.
Highlights
The evolution of resistance to antibiotics impedes treatment of infections [1]
Contrary to our expectation that pleiotropic effects of antibiotic resistance would alter responses to lytic phages, we found only weak effects on growth and adaptation to phage treatments
The strongest effect for an antibiotic-resistance allele (K43N with phage T4) was linked to a relatively large growth cost in the absence of phages that was in turn associated with relatively infrequent resistance evolution against some phages
Summary
The evolution of resistance to antibiotics impedes treatment of infections [1]. Lytic bacteriophages, which are abundant in nature and clinically relevant environments including the human gut [2], are regarded as a promising alternative or adjunct [3,4]. Altered sensitivity to phages might result, for example, from wide-ranging pleiotropic changes in gene expression caused by some antibiotic-resistance alleles [6] These pleiotropic effects could influence rates of phage-resistance evolution, if they alter the frequencies or fitness effects of phage-resistance mutations. Even if this is not the case, antibiotic resistance is frequently associated with reduced bacterial population growth [7], potentially inhibiting phage-resistance evolution by reducing mutation supply. — mutS gyrA gyrA rpoB rpoB rpsL rpsL plasmid plasmid antibiotic resistance ‘sensitive’ Kan Cipro Cipro Rif Rif Strep Strep Strep þ Sulf Tet þ Amp þ Kan We tested this by quantifying the effect of resistance mechanisms against several antibiotics, encoded by either chromosomal mutations or plasmids, on bacterial growth and resistance evolution in phage treatments. Because changes in mutation rate resulting from antibiotic-resistance alleles or mutator alleles may vary across genes or phenotypes [16], we tested each bacteria  phage combination separately
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