Compensatory Mutations, Antibiotic Resistance and the Population Genetics of Adaptive Evolution in Bacteria

Abstract

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these “costs of resistance” in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

Transmission of Antimicrobial Resistant Yersinia pestis During a Pneumonic Plague Outbreak

“…The rpsL mutation conferring resistance to streptomycin, which has occurred independently at least 3 times in Y. pestis , has no detectable impact on fitness or virulence, as indicated by normal laboratory growth by strains containing this mutation and their ability to still cause animal and human disease. All growth rates examined here were similar among strains with and without this mutation and it remained fixed despite multiple laboratory passages without streptomycin, suggesting no impact on fitness, at least under tested conditions; revertants to wild type are rare in other species containing this same or other spontaneous rpsL mutations [ 32 , 33 ]. The 5 human cases documented to be infected with Y. pestis containing this mutation all rapidly progressed to acute disease and exhibited multiple symptoms upon presentation, demonstrating this AMR strain remains highly virulent in humans.…”

Open Quasispecies Systems: New Approach to Evolutionary Adaptation

“…Matrix D −1 Q m is positive, hence, Frobenius-Perron theorem suggests λ > 0, ū > 0. However, (9) gives S ≥ 0. Let us show that the latter holds if the diagonal elements of the matrix D are small enough.…”

“…However, this assumption can misrepresent the biological picture, and it is often crucial to take growth and mortality properties into account [5,6,7,8]. One of the examples, when we need a more accurate model, is bacterial population dynamics under medical treatment [9]. In this scenario, death rates are inhomogeneous since the therapeutic effect is targeting specific pathogenic types.…”

Maximum levels of cross‐contamination for 24 antimicrobial active substances in non‐target feed. Part 1: Methodology, general data gaps and uncertainties

“…This probability will depend on several complex evolutionary and ecological factors, including both the bacterial and host population structure, fitness of the resistant mutants in different environments, environmental conditions such as microbiota, levels of nutrients and selectors such as antimicrobial agents as well as other factors (see e.g. Levin et al., 2000 ; Patwa and Wahl, 2008 ; Hiltunen et al., 2017 ; Lakshmaiah Narayana et al., 2020 ; Leónidas Cardoso et al., 2020 ). In this opinion, the main focus is on determining the lowest level of an antimicrobial agent that can enrich for a specific resistant mutant under defined experimental conditions in laboratory settings.…”