Abstract
Mathematical models predict that the future of the multidrug-resistant tuberculosis epidemic will depend on the fitness cost of drug resistance. We show that in laboratory-derived mutants of Mycobacterium tuberculosis, rifampin resistance is universally associated with a competitive fitness cost and that this cost is determined by the specific resistance mutation and strain genetic background. In contrast, we demonstrate that prolonged patient treatment can result in multidrug-resistant strains with no fitness defect and that strains with low- or no-cost resistance mutations are also the most frequent among clinical isolates.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Substitution
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Antibiotics, Antitubercular / pharmacology*
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Antibiotics, Antitubercular / therapeutic use
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Bacterial Proteins / genetics
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DNA-Directed RNA Polymerases / genetics
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Drug Resistance, Multiple, Bacterial*
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Humans
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Models, Biological
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Mutation
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Mutation, Missense
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Mycobacterium tuberculosis / drug effects*
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Mycobacterium tuberculosis / genetics
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Mycobacterium tuberculosis / growth & development*
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Rifampin / pharmacology*
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Rifampin / therapeutic use
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Tuberculosis, Multidrug-Resistant / drug therapy
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Tuberculosis, Multidrug-Resistant / microbiology*
Substances
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Antibiotics, Antitubercular
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Bacterial Proteins
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rpoB protein, Mycobacterium tuberculosis
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DNA-Directed RNA Polymerases
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RNA polymerase beta subunit
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Rifampin