Abstract
ABSTRACTThe spread of antibiotic resistance is driving interest in new approaches to control bacterial pathogens. This includes applying multiple antibiotics strategically, using bacteriophages against antibiotic-resistant bacteria, and combining both types of antibacterial agents. All these approaches rely on or are impacted by associations among resistance phenotypes (where bacteria resistant to one antibacterial agent are also relatively susceptible or resistant to others). Experiments with laboratory strains have shown strong associations between some resistance phenotypes, but we lack a quantitative understanding of associations among antibiotic and phage resistance phenotypes in natural and clinical populations. To address this, we measured resistance to various antibiotics and bacteriophages for 94 natural and clinical Escherichia coli isolates. We found several positive associations between resistance phenotypes across isolates. Associations were on average stronger for antibacterial agents of the same type (antibiotic-antibiotic or phage-phage) than different types (antibiotic-phage). Plasmid profiles and genetic knockouts suggested that such associations can result from both colocalization of resistance genes and pleiotropic effects of individual resistance mechanisms, including one case of antibiotic-phage cross-resistance. Antibiotic resistance was predicted by core genome phylogeny and plasmid profile, but phage resistance was predicted only by core genome phylogeny. Finally, we used observed associations to predict genes involved in a previously uncharacterized phage resistance mechanism, which we verified using experimental evolution. Our data suggest that susceptibility to phages and antibiotics are evolving largely independently, and unlike in experiments with lab strains, negative associations between antibiotic resistance phenotypes in nature are rare. This is relevant for treatment scenarios where bacteria encounter multiple antibacterial agents.
Highlights
The spread of antibiotic resistance is driving interest in new approaches to control bacterial pathogens
We found that isolates with similar plasmid replicon profiles (Fig. 3) had similar antibiotic resistance profiles
Associations among resistance phenotypes are known to be central to the success of some promising novel approaches to treatment, such as combining antibiotics in ways that minimize the spread of resistance [41] and applying phages as a complement or alternative to antibiotics [5]
Summary
The spread of antibiotic resistance is driving interest in new approaches to control bacterial pathogens. Analysis of bacterial genome sequences and horizontally transferred genetic elements (plasmids) helped to explain this, as well as our finding that there was no overall association between antibiotic resistance and bacteriophage resistance profiles across isolates This improves our understanding of resistance evolution in nature, potentially informing new rational therapies that combine different antibacterials, including bacteriophages. In vitro experiments with resistant mutants isolated from lab strains suggest that such negative associations are quite common [12], it remains unclear whether these effects apply in natural populations [13, 14] Exploiting these effects in novel multidrug treatments depends critically on whether they apply to other types of resistance elements such as plasmids that are central to the evolution and spread of resistance in pathogens such as Escherichia coli [15]. We assessed the strength of nonrandom associations between resistance phenotypes while accounting for core genome phy-
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