The Role of Compensatory Mutations in the Emergence of Drug Resistance

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Abstract
Pathogens that evolve resistance to drugs usually have reduced fitness. However, mutations that largely compensate for this reduction in fitness often arise. We investigate how these compensatory mutations affect population-wide resistance emergence as a function of drug treatment. Using a model of gonorrhea transmission dynamics, we obtain generally applicable, qualitative results that show how compensatory mutations lead to more likely and faster resistance emergence. We further show that resistance emergence depends on the level of drug use in a strongly nonlinear fashion. We also discuss what data need to be obtained to allow future quantitative predictions of resistance emergence. Pathogens that evolve resistance to drugs pose a serious public health problem. Acquisition of drug resistance usually leads to a pathogen which in the absence of the drug is less fit than the nonresistant pathogen. However, the resistant pathogen can undergo additional mutations that compensate for the fitness cost involved with acquisition of resistance. This can result in a drug-resistant pathogen with fitness comparable to that of the nonresistant pathogen. Handel, Regoes, and Antia analyzed a mathematical model to explain how this process of compensatory mutations influences the probability of and time to resistance emergence on a population level. The authors found that with compensatory mutations, resistance emergence is faster and more likely. Their study also shows how small changes in levels of treatment can lead to large changes in the time to resistance emergence. They further discuss how our ability to accurately predict resistance emergence will depend on improved estimates of the parameters governing the processes of resistance acquisition and compensatory mutations. The study suggests that compensatory mutations can play an important role in the evolution and spread of resistant pathogens through a population.