Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost i ll the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia col i, HIV, and Salmonella typhimurium found that evolution in the absence of t hese drugs commonly results in the ascent of mutations that ameliorate thes e costs, rather than higher-fitness, drug-sensitive revertants. To ascertai n the conditions under which this compensatory evolution, rather than rever sion, will occur, we did computer simulations, in vitro, experiments, and D NA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutant s of E, coli with and without mutations that compensate for the fitness cos ts of these ribosomal protein mutations. The results of our investigation s upport,rt the hypothesis that in these experiments, the ascent of intermedi ate-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 o f parasitic and commensal microbes and discuss the implications of these re sults to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.