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Publicação
Positive Epistasis Drives the Acquisition of Multidrug Resistance
Orientador(es)
Resumo(s)
The evolution of multiple antibiotic resistance is an increasing global problem.
Resistance mutations are known to impair fitness, and the evolution of
resistance to multiple drugs depends both on their costs individually and on how
they interact-epistasis. Information on the level of epistasis between
antibiotic resistance mutations is of key importance to understanding epistasis
amongst deleterious alleles, a key theoretical question, and to improving public
health measures. Here we show that in an antibiotic-free environment the cost of
multiple resistance is smaller than expected, a signature of pervasive positive
epistasis among alleles that confer resistance to antibiotics. Competition
assays reveal that the cost of resistance to a given antibiotic is dependent on
the presence of resistance alleles for other antibiotics. Surprisingly we find
that a significant fraction of resistant mutations can be beneficial in certain
resistant genetic backgrounds, that some double resistances entail no measurable
cost, and that some allelic combinations are hotspots for rapid compensation.
These results provide additional insight as to why multi-resistant bacteria are
so prevalent and reveal an extra layer of complexity on epistatic patterns
previously unrecognized, since it is hidden in genome-wide studies of genetic
interactions using gene knockouts.
Descrição
Palavras-chave
antibiotic-resistance, escherichia-coli, mycobacterium-tuberculosis, deleterious mutations, compensatory mutations, fitness costs, evolution,
adaptation, bacteria
Contexto Educativo
Citação
Editora
Public Library of Science (PLoS)