Efflux-linked accelerated evolution of antibiotic resistance at a population edge

• Published in: Molecular cell 2022-11, Vol.82 (22), p.4368-4385.e6
• Main Authors: Bhattacharyya, Souvik, Bhattacharyya, Madhumita, Pfannenstiel, Dylan M., Nandi, Anjan K., Hwang, YuneSahng, Ho, Khang, Harshey, Rasika M.
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; antibiotic resistance; Bacteria - genetics; Biological Transport; DNA repair; Drug Resistance, Microbial; efflux; EPI; evolution; iron acquisition; mutation; necrosignal; ROS; swarming
• ISSN: 1097-2765; 1097-4164
• DOI: 10.1016/j.molcel.2022.10.024

Efflux is a common mechanism of resistance to antibiotics. We show that efflux itself promotes accumulation of antibiotic-resistance mutations (ARMs). This phenomenon was initially discovered in a bacterial swarm where the linked phenotypes of high efflux and high mutation frequencies spatially segregated to the edge, driven there by motility. We have uncovered and validated a global regulatory network connecting high efflux to downregulation of specific DNA-repair pathways even in non-swarming states. The efflux-DNA repair link was corroborated in a clinical “resistome” database: genomes with mutations that increase efflux exhibit a significant increase in ARMs. Accordingly, efflux inhibitors decreased evolvability to antibiotic resistance. Swarms also revealed how bacterial populations serve as a reservoir of ARMs even in the absence of antibiotic selection pressure. High efflux at the edge births mutants that, despite compromised fitness, survive there because of reduced competition. This finding is relevant to biofilms where efflux activity is high. [Display omitted] •A common mechanism of bacterial resistance to antibiotics is drug efflux•High efflux is linked to downregulation of DNA repair and is therefore mutagenic•Inhibitors that target efflux decrease evolvability to antibiotic resistance•Efflux activity creates a high-evolvability niche at a population edge Bacteria commonly resist antibiotic treatment by activating efflux pumps to flush out the antibiotic. Bhattacharyya et al. show that a downside to this action is suppression of DNA repair, leading to acquisition of genetic resistance to the antibiotic. Their work provides leads for interfering with evolvability to drug resistance.