Targeting evolution to inhibit antibiotic resistance

Drug‐resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less subject to existing resistance mechanisms, history shows that this strategy by itself is unlikely to solve the problem of drug resist...

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Bibliographic Details
Published in:The FEBS journal Vol. 287; no. 20; pp. 4341 - 4353
Main Authors: Merrikh, Houra, Kohli, Rahul M.
Format: Journal Article
Language:English
Published: England Blackwell Publishing Ltd 01.10.2020
Subjects:
Antibiotic resistance
Antibiotics
Bacterial diseases
Drug development
Drug resistance
drugs
Evolution
Genetic diversity
genetic variation
Global health
Mfd
Mutagenesis
mutagens
Public health
Resistance factors
RpoS
SOS response
stress response
Therapeutic targets
therapeutics
transcription‐associated mutagenesis
stress response
RpoS
antibiotic resistance
Mfd
SOS response
evolution
transcription-associated mutagenesis
mutagenesis
ISSN:1742-464X, 1742-4658, 1742-4658
Online Access:Get full text
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Summary:Drug‐resistant bacterial infections have led to a global health crisis. Although much effort is placed on the development of new antibiotics or variants that are less subject to existing resistance mechanisms, history shows that this strategy by itself is unlikely to solve the problem of drug resistance. Here, we discuss inhibiting evolution as a strategy that, in combination with antibiotics, may resolve the problem. Although mutagenesis is the main driver of drug resistance development, attacking the drivers of genetic diversification in pathogens has not been well explored. Bacteria possess active mechanisms that increase the rate of mutagenesis, especially at times of stress, such as during replication within eukaryotic host cells, or exposure to antibiotics. We highlight how the existence of these promutagenic proteins (evolvability factors) presents an opportunity that can be capitalized upon for the effective inhibition of drug resistance development. To help move this idea from concept to execution, we first describe a set of criteria that an ‘optimal’ evolvability factor would likely have to meet to be a viable therapeutic target. We then discuss the intricacies of some of the known mutagenic mechanisms and evaluate their potential as drug targets to inhibit evolution. In principle, and as suggested by recent studies, we argue that the inhibition of these and other evolvability factors should reduce resistance development. Finally, we discuss the challenges of transitioning anti‐evolution drugs from the laboratory to the clinic. Bacteria can activate a variety of mechanisms to accelerate their access to genotypic variants, some of which can convert antibiotic‐susceptible bacteria into antibiotic‐resistant ones. These active mutagenesis mechanisms are ripe candidates for the development of anti‐evolutionary therapies, offering a novel and needed and novel approach to combating the challenge of antibiotic resistance.
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HM and RMK developed the concepts together and wrote the manuscript.
Author Contributions
ISSN:1742-464X
1742-4658
1742-4658
DOI:10.1111/febs.15370