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From the soil to the clinic: the impact of microbial secondary metabolites on antibiotic tolerance and resistance

Abstract

Secondary metabolites profoundly affect microbial physiology, metabolism and stress responses. Increasing evidence suggests that these molecules can modulate microbial susceptibility to commonly used antibiotics; however, secondary metabolites are typically excluded from standard antimicrobial susceptibility assays. This may in part account for why infections by diverse opportunistic bacteria that produce secondary metabolites often exhibit discrepancies between clinical antimicrobial susceptibility testing results and clinical treatment outcomes. In this Review, we explore which types of secondary metabolite alter antimicrobial susceptibility, as well as how and why this phenomenon occurs. We discuss examples of molecules that opportunistic and enteric pathogens either generate themselves or are exposed to from their neighbours, and the nuanced impacts these molecules can have on tolerance and resistance to certain antibiotics.

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Fig. 1: Secondary metabolite-mediated regulation of multidrug resistance efflux pumps.
Fig. 2: Secondary metabolite interactions with oxidative stress.
Fig. 3: Secondary metabolites as interspecies modulators of antibiotic resilience.

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Acknowledgements

Work in the corresponding author’s laboratory was supported by grants to D.K.N. from the NIH (1R01AI127850-01A1, 1R01HL152190-01) and the Doren Family Foundation. E.K.P. was supported by a National Science Foundation Graduate Research Fellowship under Grant No. DGE-1745301.

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E.K.P., L.A.M. and D.K.N. conceived the idea. E.K.P. and L.A.M. wrote the paper. D.K.N. edited the paper.

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Correspondence to Dianne K. Newman.

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Nature Reviews Microbiology thanks B. Luisi, who co-reviewed with Y. Ntsogo and E. Petsolari; and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Tolerance

The ability to survive transient antibiotic exposure.

Resistance

The ability to grow in the presence of antibiotics at a given concentration.

Antibiotic resilience

The ability of a bacterial population to be refractory to antibiotic treatment via tolerance and/or resistance.

Efflux pumps

Membrane-associated transport proteins that are responsible for the extrusion of various compounds out of the cell.

Persisters

A subpopulation of bacteria that is killed by a given antibiotic at a much slower rate than the rest of the population, in a manner that is non-heritable.

Antioxidant activity

The ability to neutralize highly reactive free radicals.

Pro-oxidant activity

The ability to induce oxidative stress.

Polymicrobial infection

An infection that is caused by more than one species of microorganism.

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Perry, E.K., Meirelles, L.A. & Newman, D.K. From the soil to the clinic: the impact of microbial secondary metabolites on antibiotic tolerance and resistance. Nat Rev Microbiol (2021). https://doi.org/10.1038/s41579-021-00620-w

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