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Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance.

ABSTRACT: Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe Escherichia coli phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopolysaccharide (LPS). Since TolC and LPS contribute to antibiotic resistance, phage U136B should select for their loss or modification, thereby driving a trade-off between phage resistance and either of the antibiotic resistance mechanisms. To test this hypothesis, we used fluctuation experiments and experimental evolution to obtain phage-resistant mutants. Using these mutants, we compared the accessibility of specific mutations (revealed in the fluctuation experiments) to their actual success during ecological competition and coevolution (revealed in the evolution experiments). Both tolC and LPS-related mutants arise readily during fluctuation assays, with tolC mutations becoming more common during the evolution experiments. In support of the trade-off hypothesis, phage resistance via tolC mutations occurs with a corresponding reduction in antibiotic resistance in many cases. However, contrary to the hypothesis, some phage resistance mutations pleiotropically confer increased antibiotic resistance. We discuss the molecular mechanisms underlying this surprising pleiotropic result, consideration for applied phage biology, and the importance of ecology in evolution of phage resistance. We envision that phages may be useful for the reversal of antibiotic resistance, but such applications will need to account for unexpected pleiotropy and evolutionary context.

SUBMITTER: Burmeister AR

PROVIDER: S-EPMC7260982 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance.

Burmeister Alita R AR Fortier Abigail A Roush Carli C Lessing Adam J AJ Bender Rose G RG Barahman Roxanna R Grant Raeven R Chan Benjamin K BK Turner Paul E PE

Proceedings of the National Academy of Sciences of the United States of America 20200518 21

Bacteria frequently encounter selection by both antibiotics and lytic bacteriophages. However, the evolutionary interactions between antibiotics and phages remain unclear, in particular, whether and when phages can drive evolutionary trade-offs with antibiotic resistance. Here, we describe <i>Escherichia coli</i> phage U136B, showing it relies on two host factors involved in different antibiotic resistance mechanisms: 1) the efflux pump protein TolC and 2) the structural barrier molecule lipopol ...[more]

PMID: 32424102

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Project description:Although antibiotics are the primary method against bacterial infections, the rapid emergence of antibiotic resistance has forced interest in alternative antimicrobial strategies. Phage has been considered a new biological antimicrobial agent due to its high effectiveness in treating bacterial infections. However, the applications of phage therapy have been limited by the quick development of phage-resistant bacteria. Therefore, more effective phage treatment strategies need to be explored guided by characterizing phage-resistant mutants. In this study, Pseudomonas plecoglossicida phage vB_PpS_SYP was isolated from the sewage but exhibited weak antibacterial activity caused by phage-resistant bacteria. Phage-resistant mutants were isolated and their whole genomes were analyzed for differences. The results showed that mutations in glycosyltransferase family 1 (GT-1) and hypothetical outer membrane protein (homP) led to bacterial phage resistance. The GT-1 mutants had lower biofilm biomass and higher antibiotic sensitivity than wild-type strain. Phage SYP evolved a broader host range and improved antimicrobial efficacy to infect homP mutants. Therefore, we designed a strategy for combined antibiotic and evolved phage inhibition driven by the two phage-resistant mutants. The results showed that the combination was more effective against bacteria than either antibiotics or phage alone. Our findings presented a novel approach to utilizing poorly antimicrobial phages by characterizing their phage-resistant mutants, with the potential to be expanded to include phage therapy for a variety of pathogens. IMPORTANCE The rapid emergence of antibiotic resistance renews interest in phage therapy. However, the lack of efficient phages against bacteria and the emergence of phage resistance impaired the efficiency of phage therapy. In this study, the isolated Pseudomonas plecoglossicida phage exhibited poor antibacterial capacity and was not available for phage therapy. Analysis of phage-resistant mutants guided the design of antibacterial strategies for the combination of antibiotics with evolved phages. The combination has a good antibacterial effect compared to the original phage. Our findings facilitate ideas for the development of antimicrobial-incapable phage, which have the potential to be applied to the phage treatment of other pathogens.

Project description:BackgroundEfflux is a widespread mechanism of reversible drug resistance in bacteria that can be triggered by environmental stressors, including many classes of drugs. While such chemicals when used alone are typically toxic to the cell, they can also induce the efflux of a broad range of agents and may therefore prove beneficial to cells in the presence of multiple stressors. The cellular response to a combination of such chemical stressors may be governed by a trade-off between the fitness costs due to drug toxicity and benefits mediated by inducible systems. Unfortunately, disentangling the cost-benefit interplay using measurements of bacterial growth in response to the competing effects of the drugs is not possible without the support of a theoretical framework.ResultsHere, we use the well-studied multiple antibiotic resistance (MAR) system in E. coli to experimentally characterize the trade-off between drug toxicity ("cost") and drug-induced resistance ("benefit") mediated by efflux pumps. Specifically, we show that the combined effects of a MAR-inducing drug and an antibiotic are governed by a superposition of cost and benefit functions that govern these trade-offs. We find that this superposition holds for all drug concentrations, and it therefore allows us to describe the full dose-response diagram for a drug pair using simpler cost and benefit functions. Moreover, this framework predicts the existence of optimal growth at a non-trivial concentration of inducer. We demonstrate that optimal growth does not coincide with maximum induction of the mar promoter, but instead results from the interplay between drug toxicity and mar induction. Finally, we derived and experimentally validated a general phase diagram highlighting the role of these opposing effects in shaping the interaction between two drugs.ConclusionsOur analysis provides a quantitative description of the MAR system and highlights the trade-off between inducible resistance and the toxicity of the inducing agent in a multi-component environment. The results provide a predictive framework for the combined effects of drug toxicity and induction of the MAR system that are usually masked by bulk measurements of bacterial growth. The framework may also be useful for identifying optimal growth conditions in more general systems where combinations of environmental cues contribute to both transient resistance and toxicity.

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Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance.

Publications

Pleiotropy complicates a trade-off between phage resistance and antibiotic resistance.

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