PT  - JOURNAL ARTICLE
AU  - Jeff Maltas
AU  - Kevin B. Wood
TI  - Dynamic collateral sensitivity profiles highlight challenges and opportunities for optimizing antibiotic sequences
AID  - 10.1101/2021.12.19.473361
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2021.12.19.473361
4099  - http://biorxiv.org/content/early/2021/12/21/2021.12.19.473361.short
4100  - http://biorxiv.org/content/early/2021/12/21/2021.12.19.473361.full
AB  - As traditional antimicrobial therapies fail at escalating rates, recent focus has shifted to evolution-based therapies to slow resistance. Collateral sensitivity–the increased susceptibility to one drug associated with evolved resistance to a different drug–offers a potentially exploitable evolutionary constraint, but the manner in which collateral effects emerge over time is not well understood. Here, we use laboratory evolution in the opportunistic pathogen E. faecalis to phenotypically characterize collateral profiles through evolutionary time. Specifically, we measure collateral profiles for 400 strain-antibiotic combinations over the course of 4 evolutionary time points as strains are selected in increasing concentrations of antibiotic. We find that collateral resistance dominates during early phases of adaptation, whereas a diverse set of collateral profiles are accessible with further selection. Using simple numerical simulations, we illustrate how these temporally dynamic profiles potentially impact sequential drug therapies. Finally, we show experimentally how dynamic collateral sensitivity relationships can create optimal dosing windows that depend on finely timed switching between drugs.Competing Interest StatementThe authors have declared no competing interest.