TY - JOUR T1 - Conserved collateral susceptibility networks in diverse clinical strains of <em>Escherichia coli</em> JF - bioRxiv DO - 10.1101/248872 SP - 248872 AU - Nicole L. Podnecky AU - Elizabeth G. A. Fredheim AU - Julia Kloos AU - Vidar Sørum AU - Raul Primicerio AU - Adam P. Roberts AU - Daniel E. Rozen AU - Ørjan Samuelsen AU - Pål J. Johnsen Y1 - 2018/01/01 UR - http://biorxiv.org/content/early/2018/01/17/248872.abstract N2 - 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. ER -