Evolutionary stability of collateral sensitivity to antibiotics in the model pathogenPseudomonas aeruginosa

Abstract

24Evolution is at the core of the impending antibiotic crisis. Sustainable therapy must thus 25 account for the adaptive potential of pathogens. One option is to exploit evolutionary trade-26 offs, like collateral sensitivity, where evolved resistance to one antibiotic causes 27 hypersensitivity to another one. To date, the evolutionary stability and thus clinical utility of 28 this trade-off is unclear. We performed a critical experimental test on this key requirement, 29using evolution experiments with Pseudomonas aeruginosa combined with genomic and 30 genetic analyses, and identified three main outcomes: (i) bacteria commonly failed to 31 counter hypersensitivity and went extinct; (ii) hypersensitivity sometimes converted into 32 multidrug resistance; and (iii) resistance gains occasionally caused re-sensitization to the 33 previous drug, thereby maintaining the trade-off. Drug order affected the evolutionary 34 outcome, most likely due to variation in fitness costs and epistasis among adaptive 35mutations. Our finding of robust genetic trade-offs and drug-order effects can guide design 36 of evolution-informed antibiotic therapy.

Impacts of pathogen-host-drug interaction in the evolution and spread of antimicrobial-resistant pathogens

“…Currently, the bacteria evolution in multidrug environment is one of the major causes of drug resistance, whereby drug resistance mediated mutations become resistant to multiple drugs and can no longer be destroyed using the current antibiotic drug combination treatment approaches as it is [11]. Moreover, even though a patient who have been treated with drug combination therapy, the antimicrobial resistance pathogens including M. tuberculosis increase time to time and evolved into many multidrug and extensively drug-resistant strains, and achieving the STOP/End-TB strategy at the global level by 2035/2050 remains questionable and challenging, it is important to understand what are and how the influencing factors in multi-drug environment change treatment efficacy [12], that needs for designing novel effective drug [13] suggested that the proper selection of antibiotic drug combination therapy at the right dose and for the right length of time for crucial treatment efficacy, and necessitates by understanding the potential mechanisms of the influencing factors such as epistatic pathogen-host-antibiotic interactions and the frequency of mutations with pleiotropic fitness effects is the current critical and serious tasks in order to treat the patients efficiently and to slowdown the emergency and evolution of multidrugresistance bacterial strains, when the combined inhibitory effect of two drugs are stronger for their ability to clear infections under multi-drug environment [2].…”