The Competitive Cost of Antibiotic Resistance in Mycobacterium tuberculosis
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.
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Compensatory mutations may subsequently arise to offset the major fitness cost of mutations conferring drug resistance.
“suggesting that compensatory mutations may subsequently arise to offset the major fitness cost of mutations conferring drug”
From The evolution of drug resistance in clinical isolates of Candida albicans. (2015) · cites this paper as Gagneux et al., 2006
Cites
Lenski, R. E., Rose, M. R., Simpson, S. C., & Tadler, S. C. (1991) · The American Naturalist · doi:10.1086/285289 · Cited by 1,582 · see citing works
Humans as the World's Greatest Evolutionary Force
Palumbi, S. R. (2001) · Science · doi:10.1126/science.293.5536.1786 · Cited by 1,290 · see citing works
Molecular genetic basis of antimicrobial agent resistance inMycobacterium tuberculosis: 1998 update
Ramaswamy, S. V., & Musser, J. M. (1998) · Tubercle and Lung Disease · doi:10.1054/tuld.1998.0002 · Cited by 1,099 · see citing works
Variable host–pathogen compatibility in Mycobacterium tuberculosis
Gagneux, S., DeRiemer, K., Vân, T. T. T., Kato‐Maeda, M., de Jong, B. C., Narayanan, S., Nicol, M. P., Niemann, S., Kremer, K., Gutierrez, M. C., et al. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0511240103 · Cited by 984 · see citing works
Self-citationThe biological cost of antibiotic resistance
Andersson, D. I., & Levin, B. R. (1999) · Current Opinion in Microbiology · doi:10.1016/s1369-5274(99)00005-3 · Cited by 861 · see citing works
Whole-Genome Comparison ofMycobacterium tuberculosisClinical and Laboratory Strains
Fleischmann, R. D., Alland, D., Eisen, J. A., Carpenter, L. R., White, O. R., Peterson, J., DeBoy, R. T., Dodson, R. J., Gwinn, M. L., Haft, D. H., et al. (2002) · Journal of Bacteriology · doi:10.1128/jb.184.19.5479-5490.2002 · Cited by 667 · see citing works
Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori
Björkholm, B., Sjölund, M., Falk, P. G., Berg, O. G., Engstrand, L. G., & Andersson, D. I. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.241517298 · Cited by 404 · see citing works
Molecular Epidemiology of Tuberculosis
Barnes, P. F., & Cave, M. D. (2003) · New England Journal of Medicine · doi:10.1056/nejmra021964 · Cited by 390 · see citing works
Programmes and principles in treatment of multidrug-resistant tuberculosis
Mukherjee, J. S., Rich, M., Socci, A. R., Joseph, J. K., Virú, F. A. A., Shin, S. S., Furin, J. J., Becerra, M. C., Barry, D. J., Kim, J. Y., et al. (2004) · The Lancet · doi:10.1016/s0140-6736(04)15496-2 · Cited by 333 · see citing works
Erasing the World's Slow Stain: Strategies to Beat Multidrug-Resistant Tuberculosis
Dye, C., Williams, B. G., Espinal, M., & Raviglione, M. C. (2002) · Science · doi:10.1126/science.1063814 · Cited by 314 · see citing works
Modeling epidemics of multidrug-resistant M. tuberculosis of heterogeneous fitness
Cohen, T., & Murray, M. B. (2004) · Nature Medicine · doi:10.1038/nm1110 · Cited by 281 · see citing works
Compensatory Evolution in Rifampin-Resistant <i>Escherichia coli</i>
Reynolds, M. G. (2000) · Genetics · doi:10.1093/genetics/156.4.1471 · Cited by 266 · see citing works
Maisnier‐Patin, S., & Andersson, D. I. (2004) · Research in Microbiology · doi:10.1016/j.resmic.2004.01.019 · Cited by 259 · see citing works
Reducing antibiotic resistance
Schrag, S. J., & Perrot, V. (1996) · Nature · doi:10.1038/381120b0 · Cited by 258 · see citing works
Physiological Cost of Rifampin Resistance Induced In Vitro in Mycobacterium tuberculosis
Billington, O. J., McHugh, T. D., & Gillespie, S. H. (1999) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.43.8.1866 · Cited by 252 · see citing works
Tsolaki, A. G., Gagneux, S., Pym, A. S., de la Salmonière, Y.-O. L. G., Kreiswirth, B. N., van Soolingen, D., & Small, P. M. (2005) · Journal of Clinical Microbiology · doi:10.1128/jcm.43.7.3185-3191.2005 · Cited by 250 · see citing works
Self-citationEffect of rpoB Mutations Conferring Rifampin Resistance on Fitness of Mycobacterium tuberculosis
Mariam, D. H., Mengistu, Y., Hoffner, S. E., & Andersson, D. I. (2004) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.48.4.1289-1294.2004 · Cited by 248 · see citing works
Blower, S. M., & Chou, T. (2004) · Nature Medicine · doi:10.1038/nm1102 · Cited by 216 · see citing works
Fitness Cost of Chromosomal Drug Resistance-Conferring Mutations
Sander, P., Springer, B., Prammananan, T., et al. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.5.1204-1211.2002 · Cited by 214 · see citing works
Silent Nucleotide Polymorphisms and a Phylogeny for Mycobacterium tuberculosis
Baker, L. V., Brown, T., Maiden, M. C. J., & Drobniewski, F. A. (2004) · Emerging infectious diseases · doi:10.3201/eid1009.040046 · Cited by 213 · see citing works
Will tuberculosis become resistant to all antibiotics?
Dye, C., & Espinal, M. (2001) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2000.1328 · Cited by 140 · see citing works
Fitness of antibiotic-resistant microorganisms and compensatory mutations
Böttger, E. C., Springer, B., Pletschette, M., & Sander, P. (1998) · Nature Medicine · doi:10.1038/3906 · Cited by 138 · see citing works
Biological Cost of Rifampin Resistance from the Perspective of Staphylococcus aureus
Wichelhaus, T. A., Böddinghaus, B., Besier, S. M., et al. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.11.3381-3385.2002 · Cited by 113 · see citing works
AMELIORATION OF THE DELETERIOUS PLEIOTROPIC EFFECTS OF AN ADAPTIVE MUTATION INBACILLUS SUBTILIS
Cohan, F. M., King, E. C., & Zawadzki, P. (1994) · Evolution · doi:10.1111/j.1558-5646.1994.tb01296.x · Cited by 95 · see citing works
Post, F. A., Willcox, P. A., Mathema, B., et al. (2004) · The Journal of Infectious Diseases · doi:10.1086/421501 · Cited by 76 · see citing works
Overview of Resistance in the 1990s
File, T. M. (1999) · CHEST Journal · doi:10.1378/chest.115.suppl_1.3s · Cited by 74 · see citing works
O’Sullivan, D. M., McHugh, T. D., & Gillespie, S. H. (2005) · Journal of Antimicrobial Chemotherapy · doi:10.1093/jac/dki069 · Cited by 59 · see citing works
Amelioration of the Deleterious Pleiotropic Effects of an Adaptive Mutation in Bacillus subtilis
Cohan, F. M., King, E. C., & Zawadzki, P. (1994) · Evolution · doi:10.2307/2410005 · Cited by 40 · see citing works
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Ford, C. B., Shah, R. R., Maeda, M. K., Gagneux, S., Murray, M. B., Cohen, T., Johnston, J. C., Gardy, J., Lipsitch, M., & Fortune, S. M. (2013) · Nature Genetics · doi:10.1038/ng.2656 · Cited by 457 · see citing works
Self-citationThe evolution of drug resistance in clinical isolates of Candida albicans.
Ford, C. B., Funt, J. M., Abbey, D., Issi, L., Guiducci, C., Martinez, D. A., Delorey, T., Li, B. Y., White, T. C., Cuomo, C., et al. (2015) · eLife · doi:10.7554/elife.00662 · Cited by 348 · see citing works
Ferrari, S., Ischer, F., Calabrese, D., Posteraro, B., Sanguinetti, M., Fadda, G., Rohde, B., Bauser, C., Bader, O., & Sanglard, D. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000268 · Cited by 295 · see citing works
Bryant, J., Chewapreecha, C., & Bentley, S. D. (2012) · Future Microbiology · doi:10.2217/fmb.12.108 · Cited by 98 · see citing works
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Hill, J. A., O’Meara, T. R., & Cowen, L. E. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.01.009 · Cited by 80 · see citing works
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- Authors
- Gagneux, S., Long, C. D., Small, P. M., Van, T., Schoolnik, G. K., & Bohannan, B. J. M.
- Affiliations
- Division of Infectious Diseases and Geographic Medicine, Stanford University, Stanford, CA 94305, USA.
- Gates Foundation (US)
- Corresponding author
- Long, Clara Davis
- Venue
- Science
- Published
- 2006-06-30
- Volume
- 312
- Issue
- 5782
- Pages
- 1944-1946
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2090640084
- Cited by
- 627
- References
- 28
- Citations by year
- 2026: 16 · 2025: 22 · 2024: 27 · 2023: 19 · 2022: 26 · 2021: 26 · 2020: 29 · 2019: 30 · 2018: 39 · 2017: 52 · 2016: 37 · 2015: 36 · 2014: 36 · 2013: 39 · 2012: 40
- FWCI
- 18.38
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Wellcome Trust
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Health Sciences › Medicine › Surgery › Infectious Diseases and Tuberculosis
- Keywords
- Mycobacterium tuberculosis, multidrug-resistant tuberculosis, rifampicin resistance, competitive fitness, resistance mutations, long-term treatment, clinical isolates
- MeSH terms
- Antibiotics, Antitubercular, Bacterial Proteins, Humans, Models, Biological, Mutation, Mycobacterium tuberculosis, Rifampin, DNA-Directed RNA Polymerases, Tuberculosis, Multidrug-Resistant, Amino Acid Substitution, Mutation, Missense, Drug Resistance, Multiple, Bacterial
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