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The physiology and genetics of bacterial responses to antibiotic combinations

Abstract

Several promising strategies based on combining or cycling different antibiotics have been proposed to increase efficacy and counteract resistance evolution, but we still lack a deep understanding of the physiological responses and genetic mechanisms that underlie antibiotic interactions and the clinical applicability of these strategies. In antibiotic-exposed bacteria, the combined effects of physiological stress responses and emerging resistance mutations (occurring at different time scales) generate complex and often unpredictable dynamics. In this Review, we present our current understanding of bacterial cell physiology and genetics of responses to antibiotics. We emphasize recently discovered mechanisms of synergistic and antagonistic drug interactions, hysteresis in temporal interactions between antibiotics that arise from microbial physiology and interactions between antibiotics and resistance mutations that can cause collateral sensitivity or cross-resistance. We discuss possible connections between the different phenomena and indicate relevant research directions. A better and more unified understanding of drug and genetic interactions is likely to advance antibiotic therapy.

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Fig. 1: Interactions in antibiotic mixtures.
Fig. 2: Temporal interactions in sequential antibiotic encounters.
Fig. 3: Parallel SOS induction pathways in Escherichia coli.
Fig. 4: Examples of collateral sensitivity between antibiotics and underlying mechanisms.

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Acknowledgements

The authors thank B. Kavčič and H. Schulenburg for constructive feedback on the manuscript.

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R.R. and D.I.A. are involved in patent application SE 2050304-1 relating to the CombiANT method. T.B. declares no competing interests.

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Glossary

Tolerance

The capacity of a cell population to endure stressful exposure to, for example, drugs.

Loewe additivity

A null model of drug interaction that assumes that antibiotics cannot interact with themselves so that inhibitory doses are additive and form straight lines of equal inhibition on the response surface.

Bliss independence

A null model of drug interaction that assumes that antibiotics have independent modes of action so that their individual effects can be multiplied.

Cross-feeding

Increased tolerance of a bacterial strain to a drug that is caused by proximity to other strains.

Collective resistance

Interaction between bacterial strains whereby molecules produced by one strain are consumed by the other.

Cellular hysteresis

The long-lasting physiological effect of pretreatment on the tolerance of a cell population to a later treatment.

Cellular memory

A biological process that maintains information of the past.

SOS response

The bacterial response to DNA damage that involves RecA and LexA, and involves growth arrest and DNA repair.

Persister

A cell that survives an inhibitory dose of antibiotic due to phenotypic heterogeneity.

Pleiotropy

The production by a single gene or mutation of multiple effects.

Epistasis

The combined effect of two genetic entities is quantitatively different from that expected by additive interaction of the individual genetic effects.

Collateral sensitivity

Decreased tolerance to a drug that is caused by a mutation or gene conferring resistance to a different drug.

Chemical genomics

The study of effects of drugs and other chemicals on genome-wide genetic variation.

Clinical testing

A prospective or retrospective research study that tests how well a medical approach works in people by comparison with an included control group.

Pharmacodynamics

The study of the molecular action of a drug on the target organism, including binding, dose–response relations and interactions with other molecules.

Pharmacokinetics

The study of the processes in the human body that govern resorption, distribution, metabolization and excretion of a drug.

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Roemhild, R., Bollenbach, T. & Andersson, D.I. The physiology and genetics of bacterial responses to antibiotic combinations. Nat Rev Microbiol (2022). https://doi.org/10.1038/s41579-022-00700-5

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