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

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.

Automated summary

Efflux is not only a mechanism for bacteria to acquire antibiotic resistance, but also promotes the accumulation of antibiotic resistance mutations (ARMs). The study shows that high efflux leads to downregulation of specific DNA repair pathways, resulting in an increase in ARMs. Additionally, bacteria populations with high efflux serve as reservoirs of ARMs, even in the absence of antibiotic selection pressure. This finding is particularly significant for the treatment of antibiotic-resistant biofilms.