Evolution of Antibiotic Tolerance Shapes Resistance Development in ChronicPseudomonas aeruginosaInfections

Abstract

The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed in-patient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.

Essential Gene Phenotypes Reveal Antibiotic Mechanisms and Synergies inAcinetobacter baumannii

“…Mutations in nuo genes are commonly obtained in screens for tobramycin resistance in P. aeruginosa (55, 56) supporting a model in which reduced NDH-1 function decreases permeability of the inner membrane to antibiotics. Although the permeability mechanism is unknown, it is assumed that PMF-dependent transporters are responsible for tobramycin entry into the cytoplasm.…”

The secret lives of single cells

“…Similarly, breakthroughs in understanding how antibiotic resistance arises will likely be achieved by studying single cells. Currently, it is clear antibiotic resistance arises from a series of mutations in non-dormant bacteria that gradually change lag phase (Santi et al, 2021) and metabolism (Lopatkin et al, 2021). However, so far, these studies are limited to studying whole-cell populations rather than single cells.…”