Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria (original) (raw)

Abstract

In the absence of the selecting drugs, chromosomal mutations for resistance to antibiotics and other chemotheraputic agents commonly engender a cost in the fitness of microorganisms. Recent in vivo and in vitro experimental studies of the adaptation to these "costs of resistance" in Escherichia coli, HIV, and Salmonella typhimurium found that evolution in the absence of these drugs commonly results in the ascent of mutations that ameliorate these costs, rather than higher-fitness, drug-sensitive revertants. To ascertain the conditions under which this compensatory evolution, rather than reversion, will occur, we did computer simulations, in vitro experiments, and DNA sequencing studies with low-fitness rpsL (streptomycin-resistant) mutants of E. coli with and without mutations that compensate for the fitness costs of these ribosomal protein mutations. The results of our investigation support the hypothesis that in these experiments, the ascent of intermediate-fitness compensatory mutants, rather than high-fitness revertants, can be attributed to higher rates of compensatory mutations relative to that of reversion and to the numerical bottlenecks associated with serial passage. We argue that these bottlenecks are intrinsic to the population dynamics of parasitic and commensal microbes and discuss the implications of these results to the problem of drug resistance and adaptive evolution in parasitic and commmensal microorganisms in general.

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Selected References

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  1. Andersson D. I., Bohman K., Isaksson L. A., Kurland C. G. Translation rates and misreading characteristics of rpsD mutants in Escherichia coli. Mol Gen Genet. 1982;187(3):467–472. doi: 10.1007/BF00332630. [DOI] [PubMed] [Google Scholar]
  2. Austin D. J., Kakehashi M., Anderson R. M. The transmission dynamics of antibiotic-resistant bacteria: the relationship between resistance in commensal organisms and antibiotic consumption. Proc Biol Sci. 1997 Nov 22;264(1388):1629–1638. doi: 10.1098/rspb.1997.0227. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bergstrom C. T., McElhany P., Real L. A. Transmission bottlenecks as determinants of virulence in rapidly evolving pathogens. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5095–5100. doi: 10.1073/pnas.96.9.5095. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bilgin N., Claesens F., Pahverk H., Ehrenberg M. Kinetic properties of Escherichia coli ribosomes with altered forms of S12. J Mol Biol. 1992 Apr 20;224(4):1011–1027. doi: 10.1016/0022-2836(92)90466-w. [DOI] [PubMed] [Google Scholar]
  5. Björkman J., Hughes D., Andersson D. I. Virulence of antibiotic-resistant Salmonella typhimurium. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3949–3953. doi: 10.1073/pnas.95.7.3949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Bloch C. A., Rode C. K. Pathogenicity island evaluation in Escherichia coli K1 by crossing with laboratory strain K-12. Infect Immun. 1996 Aug;64(8):3218–3223. doi: 10.1128/iai.64.8.3218-3223.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Borman A. M., Paulous S., Clavel F. Resistance of human immunodeficiency virus type 1 to protease inhibitors: selection of resistance mutations in the presence and absence of the drug. J Gen Virol. 1996 Mar;77(Pt 3):419–426. doi: 10.1099/0022-1317-77-3-419. [DOI] [PubMed] [Google Scholar]
  8. Bouma J. E., Lenski R. E. Evolution of a bacteria/plasmid association. Nature. 1988 Sep 22;335(6188):351–352. doi: 10.1038/335351a0. [DOI] [PubMed] [Google Scholar]
  9. Burch C. L., Chao L. Evolution by small steps and rugged landscapes in the RNA virus phi6. Genetics. 1999 Mar;151(3):921–927. doi: 10.1093/genetics/151.3.921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Hasenbank R., Guthrie C., Stöffler G., Wittmann H. G., Rosen L., Apirion D. Electrophoretic and immunological studies on ribosomal proteins of 100 Escherichia coli revertants from streptomycin dependence. Mol Gen Genet. 1973 Dec 14;127(1):1–18. doi: 10.1007/BF00267778. [DOI] [PubMed] [Google Scholar]
  11. Lenski R. E., Travisano M. Dynamics of adaptation and diversification: a 10,000-generation experiment with bacterial populations. Proc Natl Acad Sci U S A. 1994 Jul 19;91(15):6808–6814. doi: 10.1073/pnas.91.15.6808. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Levin B. R., Bull J. J. Short-sighted evolution and the virulence of pathogenic microorganisms. Trends Microbiol. 1994 Mar;2(3):76–81. doi: 10.1016/0966-842x(94)90538-x. [DOI] [PubMed] [Google Scholar]
  13. Luria S. E., Delbrück M. Mutations of Bacteria from Virus Sensitivity to Virus Resistance. Genetics. 1943 Nov;28(6):491–511. doi: 10.1093/genetics/28.6.491. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Massad E., Lundberg S., Yang H. M. Modeling and simulating the evolution of resistance against antibiotics. Int J Biomed Comput. 1993 Jul;33(1):65–81. doi: 10.1016/0020-7101(93)90060-j. [DOI] [PubMed] [Google Scholar]
  15. Rosset R., Gorini L. A ribosomal ambiguity mutation. J Mol Biol. 1969 Jan 14;39(1):95–112. doi: 10.1016/0022-2836(69)90336-2. [DOI] [PubMed] [Google Scholar]
  16. Schrag S. J., Perrot V., Levin B. R. Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc Biol Sci. 1997 Sep 22;264(1386):1287–1291. doi: 10.1098/rspb.1997.0178. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Schrag S. J., Perrot V. Reducing antibiotic resistance. Nature. 1996 May 9;381(6578):120–121. doi: 10.1038/381120b0. [DOI] [PubMed] [Google Scholar]
  18. Stephan W. The rate of compensatory evolution. Genetics. 1996 Sep;144(1):419–426. doi: 10.1093/genetics/144.1.419. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Stewart F. M., Antia R., Levin B. R., Lipsitch M., Mittler J. E. The population genetics of antibiotic resistance. II: Analytic theory for sustained populations of bacteria in a community of hosts. Theor Popul Biol. 1998 Apr;53(2):152–165. doi: 10.1006/tpbi.1997.1352. [DOI] [PubMed] [Google Scholar]
  20. Stewart F. M., Gordon D. M., Levin B. R. Fluctuation analysis: the probability distribution of the number of mutants under different conditions. Genetics. 1990 Jan;124(1):175–185. doi: 10.1093/genetics/124.1.175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Zengel J. M., Young R., Dennis P. P., Nomura M. Role of ribosomal protein S12 in peptide chain elongation: analysis of pleiotropic, streptomycin-resistant mutants of Escherichia coli. J Bacteriol. 1977 Mar;129(3):1320–1329. doi: 10.1128/jb.129.3.1320-1329.1977. [DOI] [PMC free article] [PubMed] [Google Scholar]