The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis
Sebastien Gagneux,1,4*
Clara Davis Long,2*
Peter M. Small,4,5
Tran Van,1
Gary K. Schoolnik,1,3
Brendan J. M. Bohannan2
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.
1 Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA.
2 Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA.
3 Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
4 Institute for Systems Biology, Seattle, WA 98103, USA.
5 Bill and Melinda Gates Foundation, Seattle, WA 98102, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: sgagneux{at}systemsbiology.org
