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Antibiotic tolerance and persistence have distinct fitness trade-offs.

ABSTRACT: Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the two phenomena is their distinct penetrance within an isogenic population. While with antibiotic persistence, susceptible and persister cells co-exist, antibiotic tolerance affects the entire bacterial population. Here, we show that antibiotic tolerance can be achieved in numerous non-specific ways in vitro and during infection. More importantly, we highlight that, due to their impact on the entire bacterial population, these tolerance-inducing conditions completely mask persistence and the action of its molecular determinants. Finally, we show that even though tolerant populations display a high survival rate under bactericidal drug treatment, this feature comes at the cost of having impaired proliferation during infection. In contrast, persistence is a risk-limiting strategy that allows bacteria to survive antibiotic treatment without reducing the ability of the population to colonize their host. Altogether, our data emphasise that the distinction between these phenomena is of utmost importance to improve the design of more efficient antibiotic therapies.

SUBMITTER: Michaux C

PROVIDER: S-EPMC9704765 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Antibiotic tolerance and persistence have distinct fitness trade-offs.

Michaux Charlotte C Ronneau Séverin S Giorgio Rachel T RT Helaine Sophie S

PLoS pathogens 20221114 11

Genetically susceptible bacteria can escape the action of bactericidal antibiotics through antibiotic tolerance or persistence. However, one major difference between the two phenomena is their distinct penetrance within an isogenic population. While with antibiotic persistence, susceptible and persister cells co-exist, antibiotic tolerance affects the entire bacterial population. Here, we show that antibiotic tolerance can be achieved in numerous non-specific ways in vitro and during infection. ...[more]

PMID: 36374854

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Project description:The rapid emergence of phage-resistant bacterial mutants is a major challenge for phage therapy. Phage cocktails have been considered one approach to mitigate this issue. However, the synergistic effect of randomly selected phages in the cocktails is ambiguous. Here, we rationally designed a phage cocktail consisting of four phages that utilize the lipopolysaccharide (LPS) O antigen, the LPS outer core, the LPS inner core, and the outer membrane proteins BtuB and TolC on the Salmonella enterica serovar Enteritidis cell surface as receptors. We demonstrated that the four-phage cocktail could significantly delay the emergence of phage-resistant bacterial mutants compared to the single phage. To investigate the fitness costs associated with phage resistance, we characterized a total of 80 bacterial mutants resistant to a single phage or the four-phage cocktail. We observed that mutants resistant to the four-phage cocktail were more sensitive to several antibiotics than the single-phage-resistant mutants. In addition, all mutants resistant to the four-phage cocktail had significantly reduced virulence compared to wild-type strains. Our mouse model of Salmonella Enteritidis infection also indicated that the four-phage cocktail exhibited an enhanced therapeutic effect. Together, our work demonstrates an efficient strategy to design phage cocktails by combining phages with different bacterial receptors, which can steer the evolution of phage-resistant strains toward clinically exploitable phenotypes. IMPORTANCE The selection pressure of phage promotes bacterial mutation, which results in a fitness cost. Such fitness trade-offs are related to the host receptor of the phage; therefore, we can utilize knowledge of bacterial receptors used by phages as a criterion for designing phage cocktails. Here, we evaluated the efficacy of a phage cocktail made up of phages that target four different receptors on Salmonella Enteritidis through in vivo and in vitro experiments. Importantly, we found that pressure from phage cocktails with different receptors can drive phage-resistant bacterial mutants to evolve in a direction that entails more severe fitness costs, resulting in reduced virulence and increased susceptibility to antibiotics. These findings suggest that phage cocktail therapy using combinations of phages targeting different important receptors (e.g., LPS or the efflux pump AcrAB-TolC) on the host surface can steer the host bacteria toward more detrimental surface mutations than single-phage therapy, resulting in more favorable therapeutic outcomes.

Dataset Information

Antibiotic tolerance and persistence have distinct fitness trade-offs.

Publications

Antibiotic tolerance and persistence have distinct fitness trade-offs.

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