• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of geneticsGeneticsCurrent IssueInformation for AuthorsEditorial BoardSubscribeSubmit a Manuscript
Genetics. Dec 2000; 156(4): 1471–1481.
PMCID: PMC1461348

Compensatory evolution in rifampin-resistant Escherichia coli.


This study examines the intrinsic fitness burden associated with RNA polymerase (rpoB) mutations conferring rifampin resistance in Escherichia coli K12 (MG1655) and explores the nature of adaptation to the costs of resistance. Among 28 independent Rif(r) mutants, the per-generation fitness burden (in the absence of rifampin) ranged from 0 to 28%, with a median of 6.4%. We detected no relationship between the magnitude of the cost and the level of resistance. Adaptation to the costs of rif resistance was studied by following serial transfer cultures for several Rif(r) mutants both in the presence of rifampin and in the absence. For cultures evolved in the absence of rifampin, single clones isolated after 200 generations were more fit than their ancestor; we saw no association between increased fitness and changes in the level of rifampin resistance; and in all cases, increased fitness was due to compensatory mutations, rather than to reversion to drug sensitivity. However, in the parallel evolution experiments in the presence of rifampin, overall levels of resistance increased as did relative fitness-for all strains save one that had an initially high level of resistance. Among the evolved clones tested, five (of seven) demonstrated increased transcription efficiency (assessed using a semiquantitative RT-PCR protocol). The implications of these results for our understanding of adaptive molecular evolution and the increasing clinical problem of antibiotic resistance are discussed.

Full Text

The Full Text of this article is available as a PDF (385K).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Aubry-Damon H, Soussy CJ, Courvalin P. Characterization of mutations in the rpoB gene that confer rifampin resistance in Staphylococcus aureus. Antimicrob Agents Chemother. 1998 Oct;42(10):2590–2594. [PMC free article] [PubMed]
  • Billington OJ, McHugh TD, Gillespie SH. Physiological cost of rifampin resistance induced in vitro in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 1999 Aug;43(8):1866–1869. [PMC free article] [PubMed]
  • Björkman J, Hughes D, Andersson DI. Virulence of antibiotic-resistant Salmonella typhimurium. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3949–3953. [PMC free article] [PubMed]
  • Björkman J, Samuelsson P, Andersson DI, Hughes D. Novel ribosomal mutations affecting translational accuracy, antibiotic resistance and virulence of Salmonella typhimurium. Mol Microbiol. 1999 Jan;31(1):53–58. [PubMed]
  • Björkman J, Nagaev I, Berg OG, Hughes D, Andersson DI. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science. 2000 Feb 25;287(5457):1479–1482. [PubMed]
  • Borman AM, 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. [PubMed]
  • Filutowicz M. Requirement of DNA gyrase for the initiation of chromosome replication in Escherichia coli K-12. Mol Gen Genet. 1980 Jan;177(2):301–309. [PubMed]
  • Foley KP, Leonard MW, Engel JD. Quantitation of RNA using the polymerase chain reaction. Trends Genet. 1993 Nov;9(11):380–385. [PubMed]
  • Gong M, Cowan KH, Gudas J, Moscow JA. Isolation and characterization of genomic sequences involved in the regulation of the human reduced folate carrier gene (RFC1). Gene. 1999 Jun 11;233(1-2):21–31. [PubMed]
  • Guyer MS, Reed RR, Steitz JA, Low KB. Identification of a sex-factor-affinity site in E. coli as gamma delta. Cold Spring Harb Symp Quant Biol. 1981;45(Pt 1):135–140. [PubMed]
  • Herrera G, Aleixandra V, Urios A, Blanco M. Quinolone action in Escherichia coli cells carrying gyrA and gyrB mutations. FEMS Microbiol Lett. 1993 Jan 15;106(2):187–191. [PubMed]
  • Houze TA, Larsson L, Larsson PA, Hansson G, Asea A, Gustavsson B. Rapid detection of thymidylate synthase gene expression levels by semi-quantitative competitive reverse transcriptase polymerase chain reaction followed by quantitative digital image analysis. Tumour Biol. 1996;17(5):306–319. [PubMed]
  • Musser JM. Antimicrobial agent resistance in mycobacteria: molecular genetic insights. Clin Microbiol Rev. 1995 Oct;8(4):496–514. [PMC free article] [PubMed]
  • Padayachee T, Klugman KP. Molecular basis of rifampin resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1999 Oct;43(10):2361–2365. [PMC free article] [PubMed]
  • Pozzi G, Meloni M, Iona E, Orrù G, Thoresen OF, Ricci ML, Oggioni MR, Fattorini L, Orefici G. rpoB mutations in multidrug-resistant strains of Mycobacterium tuberculosis isolated in Italy. J Clin Microbiol. 1999 Apr;37(4):1197–1199. [PMC free article] [PubMed]
  • Reynolds MG, Roos DS. A biochemical and genetic model for parasite resistance to antifolates. Toxoplasma gondii provides insights into pyrimethamine and cycloguanil resistance in Plasmodium falciparum. J Biol Chem. 1998 Feb 6;273(6):3461–3469. [PubMed]
  • Schrag SJ, Perrot V. Reducing antibiotic resistance. Nature. 1996 May 9;381(6578):120–121. [PubMed]
  • Schrag SJ, Perrot V, Levin BR. Adaptation to the fitness costs of antibiotic resistance in Escherichia coli. Proc Biol Sci. 1997 Sep 22;264(1386):1287–1291. [PMC free article] [PubMed]
  • Weisblum B, Davies J. Antibiotic inhibitors of the bacterial ribosome. Bacteriol Rev. 1968 Dec;32(4 Pt 2):493–528. [PMC free article] [PubMed]
  • Moore FB, Rozen DE, Lenski RE. Pervasive compensatory adaptation in Escherichia coli. Proc Biol Sci. 2000 Mar 7;267(1442):515–522. [PMC free article] [PubMed]
  • Yanofsky C, Horn V. Rifampin resistance mutations that alter the efficiency of transcription termination at the tryptophan operon attenuator. J Bacteriol. 1981 Mar;145(3):1334–1341. [PMC free article] [PubMed]

Articles from Genetics are provided here courtesy of Genetics Society of America


Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...


Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...