Biology subjects

Podnecky, N. L.

Publications and source records attributed to Podnecky, N. L..

2 recordsLinked to original sources

bioRxiv2021

Evolutionary instability of collateral susceptibility networks in ciprofloxacin resistant clinical Escherichia coli strains

Collateral sensitivity and resistance occur when resistance development towards one antimicrobial either potentiates or deteriorates the effect of others, respectively. Previous reports on collateral effects on susceptibility focus on newly acquired resistance determinants and propose that novel treatment guidelines informed by collateral networks may reduce the evolution, selection and spread of antimicrobial resistance. In this study, we investigate the evolutionary stability of collateral networks in five ciprofloxacin resistant, clinical Escherichia coli strains. After 300 generations of experimental evolution without antimicrobials, we show complete fitness restoration in four of five genetic backgrounds and demonstrate evolutionary instability in collateral networks of newly acquired resistance determinants. We show that compensatory mutations reducing efflux expression is the main driver destabilizing initial collateral networks and identify rpoS as a putative target for compensatory evolution. Our results add another layer of complexity to future predictions and clinical application of collateral networks.

microbiology↗

bioRxiv2018

Conserved collateral susceptibility networks in diverse clinical strains of Escherichia coli.

There is urgent need to develop novel treatment strategies to reduce antimicrobial resistance. Collateral sensitivity (CS), where resistance to one antimicrobial increases susceptibility to other drugs, is a uniquely promising strategy that enables selection against resistance during treatment. However, using CS-informed therapy depends on conserved CS networks across genetically diverse bacterial strains. We examined CS conservation in 10 clinical strains of E. coli resistant to four clinically relevant antibiotics. Collateral susceptibilities of these 40 resistant mutants were then determined against a panel of 16 antibiotics. Multivariate statistical analyses demonstrate that resistance mechanisms, in particular efflux-related mutations, as well as relative fitness were principal contributors to collateral changes. Moreover, collateral responses shifted the mutant selection window suggesting that CS-informed therapies could affect evolutionary trajectories of antimicrobial resistance. Our data allow optimism for CS-informed therapy and further suggest that early detection of resistance mechanisms is important to accurately predict collateral antimicrobial responses.

microbiology↗