Qi, W.; Jonker, M.J.; Katsavelis, D.; de Leeuw, W.; Wortel, M.; ter Kuile, B.H. The Effect of the Stringent Response and Oxidative Stress Response on Fitness Costs of De Novo Acquisition of Antibiotic Resistance. International Journal of Molecular Sciences 2024, 25, 2582, doi:10.3390/ijms25052582.
Qi, W.; Jonker, M.J.; Katsavelis, D.; de Leeuw, W.; Wortel, M.; ter Kuile, B.H. The Effect of the Stringent Response and Oxidative Stress Response on Fitness Costs of De Novo Acquisition of Antibiotic Resistance. International Journal of Molecular Sciences 2024, 25, 2582, doi:10.3390/ijms25052582.
Qi, W.; Jonker, M.J.; Katsavelis, D.; de Leeuw, W.; Wortel, M.; ter Kuile, B.H. The Effect of the Stringent Response and Oxidative Stress Response on Fitness Costs of De Novo Acquisition of Antibiotic Resistance. International Journal of Molecular Sciences 2024, 25, 2582, doi:10.3390/ijms25052582.
Qi, W.; Jonker, M.J.; Katsavelis, D.; de Leeuw, W.; Wortel, M.; ter Kuile, B.H. The Effect of the Stringent Response and Oxidative Stress Response on Fitness Costs of De Novo Acquisition of Antibiotic Resistance. International Journal of Molecular Sciences 2024, 25, 2582, doi:10.3390/ijms25052582.
Abstract
Resistance evolution during exposure to non-lethal levels of antibiotics is influenced by various stress responses of bacteria which are known to affect growth rate. Here, we aim to disentangle how the interplay between resistance development and associated fitness costs is affected by stress responses. We performed de novo resistance evolution of wild-type strains and single-gene knockout strains in stress response pathways using four different antibiotics. Throughout resistance development, the increase in minimum inhibitory concentration (MIC) is accompanied by a gradual decrease in growth rate, most pronounced with amoxicillin or kanamycin. By measuring biomass yield on glucose and whole-genome sequences at intermediate and final timepoints, we identified two patterns of how the stress responses affect the correlation between MIC and growth rate. First, single-gene knockout E. coli strains associated with reactive oxygen species (ROS) acquire resistance faster and mutations related to antibiotic permeability and pumping out occur earlier. This increases the metabolic burden of resistant bacteria. Second, the ΔrelA knockout strain which has reduced (p)ppGpp synthesis, is restricted in its stringent response, leading to diminished growth rates. The ROS-related mutagenesis and the stringent response are vulnerabilities within the fitness of resistant strains that can possibly be targeted to prevent development of resistance.
Keywords
de novo antibiotic resistance; fitness cost; (p)ppGpp; reactive oxygen species; compensatory evolution
Subject
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
