The competitive cost of antibiotic resistance in Mycobacterium tuberculosis.
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.
Gagneux
Sebastien
S
Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA. sgagneux@systemsbiology.org
Long
Clara Davis
CD
Small
Peter M
PM
Van
Tran
T
Schoolnik
Gary K
GK
Bohannan
Brendan J M
BJ
D019943:Amino Acid Substitution; D000904:Antibiotics, Antitubercular / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000235:genetics; D012321:DNA-Directed RNA Polymerases / Q000235:genetics; D024901:Drug Resistance, Multiple, Bacterial; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D020125:Mutation, Missense; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development*; D012293:Rifampin / Q000494:pharmacology* / Q000627:therapeutic use; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology*
D000904:Antibiotics, Antitubercular; D001426:Bacterial Proteins; C505805:rpoB protein, Mycobacterium tuberculosis; D012321:DNA-Directed RNA Polymerases; C105078:RNA polymerase beta subunit; D012293:Rifampin