Chapter 27 : Evolution of Antibiotic Resistance by Hypermutation

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Antibiotic resistance may be regarded as the paradoxical consequence of the success of antibiotic therapy. Bacteria develop antibiotic resistance in two main ways: horizontal gene transfer and mutation in different chromosomal loci. The Mycobaterium tuberculosis species has to acquire antibiotic resistance by mutational events exclusively. Mutation is the raw material of evolution and is the ultimate source of heritable variation on which natural selection acts. The importance of recombination in the evolution of bacterial pathogens has become increasingly apparent. Recombination probably mediates genetic change in all bacterial species and is likely to have been crucial in allowing bacteria to avoid the immune response, in distributing among the population genes that increase virulence or transmission between hosts, and in providing increased resistance to antibiotics. A pathogen microorganism may be the paradigmatic example of a relationship between the stable hypermutation/hyperrecombination status and antibiotic resistance acquisition. This is the case of Streptococcus pneumoniae, where transformation and recombination seem to be the major sources of genetic variability. Microorganisms harboring an antibiotic-resistance mechanism, acquired either by horizontal transfer or mutation, will be positively selected in the presence of the antibiotic. It has been found that environmental and physiological stress conditions can transiently increase the mutation rate in bacteria. A number of studies strongly suggest a possible association between bacteria with high mutation rates and antibiotic-resistance acquisition.

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 1.
Figure 1.

Model for the activity of MMR in Escherichia coli. The MutS protein homodimer recognizes and binds specifically to base-base mispairing represented here as bulky triangles (a,b). This complex, by using the energy of the hydrolysis of two ATP molecules, makes a DNA loop (c). The MutL protein homodimer is then recruited, associates with this loop, and activates the endonuclease MutH (c). Activated MutH protein produces a nick in the unmethylated newly synthesized strand, which is assumed to contain the incorrect base (c). Afterwards, the nicked DNA is unbound by UvrD (helicase II) activity (d) and the cleaved strand is subjected to exonuclease degradation. The kind of exonuclease utilized in the degradative process depends on whether MutH cuts the DNA on the 5′ side of the mismatch (ExoVII or RecJ, which degrade DNA in the 5′ → 3′ direction) or the 3′ side (ExoI or ExoX, which degrade DNA in a 3′ → 5′ direction). Here, for simplicity, only one of these processes has been represented. DNA synthesis, mediated by PolIII, and DNA ligation, mediated by DNA ligase, produce a double DNA molecule free of the initial error (e). Finally, the new strand is also methylated (m) in the adenine residue in the sequence GATC by DAM methylase (f). This scheme is based on many others found in the literature, particularly from P. Modrich (Modrich, 1991).

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 2.
Figure 2.

Scheme of the SOS system describing the main molecular events that occur during the canonical SOS system induction process in E. coli. Under noninduction conditions (e.g., normal growth conditions), the cellular levels of the LexA SOS repressor are sufficient to lock a switch OFF system state. The silencing of gene SOS expression is mediated by the LexA repressor through their binding as a dimer to SOS boxes situated in the promoter region of SOS genes. For simplicity, only 4 of the 40 SOS genes have been represented. The detention of DNA replication originated by, for instance, DNA damage, generated a stalled replication fork. Single-stranded DNA (ssDNA) produced by the stalled fork is a molecular distress signal allowing the nucleation of the RecA monomer protein around the ssDNA. This process induces to the formation of a RecA filament. The interaction of ssDNA-RecA promotes the appearance of the RecA* coprotease activity. This RecA* activated molecular species promotes the autocleavage of the LexA repressor. LexA is a transcriptional regulator composed of two structurally defined domains, an N-terminal DNA-binding domain and a C-terminal dimerization domain. The cleavage in the Ala-84-Gly-85 peptide bond, situated within the hinge region that connects the two domains, liberates these two domains, thus inactivating its negative regulatory activity. This molecular inactivating process decreases the cellular level of LexA, which in turn liberates the gene SOS repression, switching the system to ON. Between the induced novel SOS functions are included two error-prone DNA polymerases, PolIV and PolV. Whereas PolIV does not require any additional processes for activation, the PolV (a heterotrimer UmuD’2UmuC) requires autocleavage of UmuD, also promoted by RecA*. The TLS (translesion synthesis) promoted by PolIV and PolV permit bypassing of the DNA lesion. Other DNA repair functions, e.g., excision repair (UvrABC) and Holliday resolution junctions (RuvAB), are also induced. Finally, when the ssDNA disappears (or the DNA damage is repaired), the level of RecA* decreases and DNA replication restarts; consequently, the level of LexA repressor increases, taking the SOS system to the OFF state.

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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Image of Figure 3.
Figure 3.

Closed circle for antibiotic resistance development (see text).

Citation: Blázquez J, Gómez-Gómez J. 2008. Evolution of Antibiotic Resistance by Hypermutation, p 319-331. In Baquero F, Nombela C, Cassell G, Gutiérrez-Fuentes J (ed), Evolutionary Biology of Bacterial and Fungal Pathogens. ASM Press, Washington, DC. doi: 10.1128/9781555815639.ch27
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1. Andersson, D. I., and, D. Hughes. 1996. Muller’s ratchet decreases fitness of a DNA-based microbe. Proc. Natl. Acad. Sci. USA 93:906907.
2. Bjorkholm, B.,, M. Sjolund,, P. G. Falk,, O. G. Berg,, L. Engstrand, and, D. I. Andersson. 2001. Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc. Natl. Acad. Sci. USA 98:1460714612.
3. Björkman, J.,, I. Nagaev,, O. G. Berg,, D. Hughes, and, D. I. Andersson. 2000. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science 287:14791482.
4. Blázquez, J. 2003. Hypermutation as a factor contributing to the acquisition of antimicrobial resistance. Clin. Infect. Dis. 37:12011209.
5. Blázquez, J.,, M. R. Baquero,, R. Cantón,, I. Alós, and, F. Baquero. 1993. Characterization of a new TEM-type β-lactamase resistant to clavulanate, sulbactam, and tazobactam in a clinical isolate of Escherichia coli. Antimicrob. Agents Chemother. 37:20592063.
6. Blázquez, J.,, L. E. Espinosa de los Monteros,, S. Samper,, C. Martín,, A. Guerrero,, J. Cobo,, J. Van Embden,, F. Baquero, and, E. Gómez-Mampaso. 1997. Genetic characterization of multidrug-resistant Mycobacterium bovis strains from a hospital outbreak involving human immunodeficiency virus-positive patients. J. Clin. Microbiol. 35:13901393.
7. Blázquez J.,, J. M. Gómez-Gómez,, A. Oliver,, C. Juan,, V. Kapur, and, S. Martín. 2006. PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa. Mol. Microbiol. 62:8499.
8. Blázquez, J.,, M. I. Morosini,, M. C. Negri, and, F. Baquero. 2000. Selection of naturally occurring extended-spectrum TEM beta-lactamase variants by fluctuating beta-lactam pressure. Antimicrob. Agents Chemother. 44:21822184.
9. Blázquez, J.,, M. I. Morosini,, M. C. Negri,, M. González-Leiza, and, F. Baquero. 1995. Single amino acid replacements at positions altered in naturally occurring extended-spectrum TEM β-lactamases. Antimicrob. Agents Chemother. 39:145149.
10. Boshoff, H. I. M.,, M. B. Reed,, C. E. Barry, III, and, V. Mizrahi. 2003. DnaE2 polymerase contributes to in vivo survival and the emergence of drug resistance in Mycobacterium tuberculosis. Cell 113:183193.
11. Böttger, E. C.,, B. Springer,, M. Pletschette, and, P. Sander. 1998. Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nat. Med. 12:13431344.
12. Brégeon, D.,, I. Matic,, M. Radman, and, F. Taddei. 1999. J. Genet. 78:2128.
13. Brown, E. W.,, J. E. LeClerc,, L. Baoguang,, W. L. Payne, and, T. A. Cebula. 2001. Phylogenetic evidence for horizontal transfer of mutS alleles among naturally occurring Escherichia coli strains. J. Bacteriol. 183:16311644.
14. Cairns, J.,, J. Overbaugh, and, S. Miller. 1988. The origin of mutants. Nature 335:142145.
15. Camas, F. M.,, J. Blázquez, and, J. F. Poyatos. 2006. Autogenous and non-autogenous control of response in a genetic network. Proc. Natl. Acad. Sci. USA 103:1271812723.
16. Chao, L., and, E. C. Cox. 1989. Competition between high and low mutating strains of Escherichia coli. Evolution 37:125.
17. Ciofu, O.,, B. Riis,, T. Pressler,, E. E. Poulsen, and, N. Hoiby. 2005. Occurrence of hypermutable Pseudomonas aeruginosa in cystic fibrosis patients is associated with the oxidative stress caused by chronic lung inflammation. Antimicrob. Agents Chemother. 49:22762282.
18. Claverys, J. P., and, S. A. Lacks. 1986. Heteroduplex deoxyribonucleic acid base mismatch repair in bacteria. Microbiol. Rev. 50:133165.
19. Claverys, J. P.,, M. Prudhomme,, I. Mortier-Barriere, and, B. Martin. 2000. Adaptation to the environment: Streptococcus pneumoniae, a paradigm for recombination-mediated genetic plasticity? Mol. Microbiol. 35:251259.
20. Coffey, T. J.,, M. Daniels,, L. K. McDougal,, C. G. Dowson,, F. C. Tenover, and, B. F. Spratt. 1995. Genetic analysis of clinical isolates of Streptococcus pneumoniae with high level resistance to expanded-spectrum cephalosporins. Antimicrob. Agents Chemother. 39:13061313.
21. Cohen, S. P.,, L. M. McMurry,, D. C. Hooper, et al. 1989. Cross-resistance to fluoroquinolones in multiple-antibiotic-resistant (Mar) Escherichia coli selected by tetracycline or chloramphenicol: decreased drug accumulation associated with membrane changes in addition to OmpF reduction. Anti-microb. Agents Chemother. 33:13181325.
22. Cooper, V. S., and, R. E Lenski. 2000. The population genetics of ecological specialization in evolving Escherichia coli populations. Nature 407:736739.
23. Courcelle, J.,, A. Khodursky,, B. Peter,, P. O. Brown, and, P. C. Hanawalt. 2001. Comparative gene expression profiles following UV exposure in wild-type and SOS-deficient Escherichia coli. Genetics 158:4164.
24. Cox, E. C., and, T. C. Gibson. 1974. Selection for high mutation rates in chemostats. Genetics 77:169184.
25. De la Cruz, F., and, J. Davies. 2000. Horizontal gene transfer and the origin of species: lessons from bacteria. Trends Microbiol. 8:128133.
26. Denamur, E.,, G. Lecointre,, P. Darlu, et al. 2000. Evolutionary implications of the frequent horizontal transfer of mismatch repair genes. Cell 103:711721.
27. Denamur, E.,, O. Tenaillon,, C. Deschamps,, D. Skurnik,, E. Ronco,, J. L. Gaillard,, B. Picard,, C. Branger, and, I. Matic. 2005. Intermediate mutation frequencies favor evolution of multidrug resistance. Genetics 171:825827.
28. Dohet, C.,, R. Wagner, and, M. Radman. 1986. Methyl-directed repair of frameshift mutations in heteroduplex DNA. Proc. Natl. Acad. Sci. USA 83:33953397.
29. Dohet, C.,, R. Wagner, and, M. Radman. 1985. Repair of defined single base-pair mismatches in Escherichia coli. Proc. Natl.Acad. Sci. USA 82:503505.
30. Dowson, C. G.,, T. J. Coffey, and, B. G. Spratt. 1994. Origin and molecular epidemiology of penicillin-binding-mediated resistance to β-lactam antibiotics. Trends Microbiol. 2:361366.
31. Drake, J. W. 1991. A constant rate of spontaneous mutation rates in DNA-based microbes. Proc. Natl. Acad. Sci. USA 88:71607164.
32. Fijalkowska, I. J., and, R. M. Schaaper. 1993. Antimutator mutations in the alfa subunit of Escherichia coli DNA polymerase III: identification of the responsible mutations and alignment with other DNA polymerases. Genetics 134:10391044.
33. Finken, M. et al. 1993. Molecular basis of streptomycin resistance in Mycobacterium tuberculosis: alterations of the ribosomal protein S12 gene and point mutations within a functional 16S ribosomal RNA pseudoknot. Mol. Microbiol. 9:12391246.
34. Fishel, R. A.,, E. C. Siegel, and, R. Kolodner. 1986. Gene conversion in Escherichia coli. Resolution of heteroallelic mismatched nucleotides by co-repair. J. Mol. Biol. 188:147157.
35. Friedberg, E. C.,, R. Wagner, and, M. Radman. 2002. Specialized DNA polymerases, cellular survival, and the genesis of mutations. Science 296:16271630.
36. Friedberg, E. C.,, G. C. Walker, and, W. Siede. 1995. DNA Repair and Mutagenesis. ASM Press, Washington, DC.
37. Funchain, P.,, A. Yeung,, J. L. Stewart,, R. Lin,, M. M. Slupska, and, J. H. Miller. 2000. The consequences of growth of a mutator strain of Escherichia coli as measured by loss of function among multiple gene targets and loss of fitness. Genetics 154:959970.
38. Garau, J.,, M. Xercavins,, M. Rodriguez-Carballeira, et al. 1999. Emergence and dissemination of quinolone-resistant Escherichia coli in the community. Antimicrob. Agents Chemother. 43:27362741.
39. Gerrish, P. J., and, R. E. Lenski. 1998. The fate of competing beneficial mutations in an asexual population. Genetica 102/103:127144.
40. Gibson, T. C.,, M. L. Scheppe, and, E. C. Cox. 1970. Fitness of an Escherichia coli mutator gene. Science 169:686688.
41. Gilligan, P. H. 1999. Microbiology of CF lung disease, p. 93114. In I. R. Yankaskas and, M. R. Knowles (ed.), Cystic Fibrosis in Adults. Lippincott, Williams & Wilkins, Philadelphia, PA.
42. Giraud, A.,, I. Matic,, M. Radman,, M. Fons, and, F. Taddei. 2002. Mutator bacteria as a risk factor in treatment of infectious diseases. Antimicrob. Agents Chemother. 46:863865.
43. Giraud, A.,, I. Matic,, O. Tenaillon,, A. Clara,, M. Radman,, M. Fons, and, F. Taddei. 2001. Costs and benefits of high mutation rates: adaptive evolution of bacteria in the mouse gut. Science 291:26062608.
44. Gómez-Gómez, J. M.,, C. Manfredi,, J. C. Alonso, and, J. Blázquez. 2007. A novel role for RecA under non-stress: promotion of swarming motility in Escherichia coli K-12. BMC Biol. 5:14.
45. Grebe, T., and, R. Hakenbeck. 1996. Penicillin-binding proteins 2b and 2x of Streptococcus pneumoniae are primary resistance determinants for different classes of beta-lactam antibiotics. Antimicrob. Agents Chemother. 40:829834.
46. Guerrero, A.,, J. Cobo,, J. Fortún,, E. Navas,, C. Quereda,, A. Asensio,, J. Cañón,, J. Blázquez, and, E. Gómez-Mampaso. 1997. Nosocomial transmission of Mycobacterium bovis resistant to 11 drugs in people with advanced HIV-1 infection. Lancet 350:17381742.
47. Horst, J. P.,, T. Wu, and, M. G. Marinus. 1999. Escherichia coli mutator genes. Trends Microbiol. 7:2936.
48. Humbert, O.,, M. Parudhomme,, R. Hakenbeck,, C. G. Dowson, and, J. P. Claverys. 1995. Homeologous recombination and mismatch repair during transformation in Streptococcus pneumoniae: saturation of the Hex mismatch repair system. Proc. Natl. Acad. Sci. USA 92:90529056.
49. Jones, M.,, R. Wagner, and, M. Radman. 1987. Repair of a mismatch is influenced by the composition of the surrounding nucleotide sequence. Genetics 115:605610.
50. Karunakaran, P., and, J. Davies. 2000. Genetic antagonism and hypermutability in Mycobacterium smegmatis. J. Bacteriol. 182:33313335.
51. Kibota, T. T., and, M. Lynch. 1996. Estimate of the genomic mutation rate deleterious to overall fitness in E. coli. Nature 381:694696.
52. Kimura, M. 1967. On the evolutionary adjustment of spontaneous mutation rates. Genet. Res. 9:2334.
53. Kohler, T.,, S. F. Epp,, L. K. Curty, and, J. C. Pechere. 1999. Characterization of MexT, the regulator of the MexE-MexF-OprN multidrug efflux system of Pseudomonas aeruginosa. J. Bacteriol. 181:63006305.
54. Kramer, B.,, W. Kramer, and, H. J. Fritz. 1984. Different base/base mismatches are corrected with different efficiencies by the methyl-directed DNA mismatch-repair system of E. coli. Cell 38:879887.
55. Kraub, J., and, R. Hakenbeck. 1997. A mutation in the D,D-carboxypeptidase penicillin-binding protein 3 of Streptococcus pneumoniae contributes to cefotaxime resistance of the laboratory mutant C604. Antimicrob. Agents Chemother. 41:936942.
56. Leclerc, J. E.,, B. Li,, W. L. Payne, and, T. A. Cebula. 1996. High mutation frequencies among Escherichia coli and Salmonella pathogens. Science 274:12081211.
57. Lederberg, J., and, E. M. Lederberg. 1952. Replica plating and indirect selection of bacterial mutants. J. Bacteriol. 63:399406.
58. Leigh, E. G. 1973. The evolution of mutation rates. Genetics 73:118.
59. Levy, D. D.,, B. Sharma, and, T. A. Cebula. 2004. Single-nucleotide polymorphism mutation spectra and resistance to quinolones in Salmonella enterica serovar Enteritidis with a mutator phenotype. Antimicrob. Agents Chemother. 48:23552363.
60. Livermore, D. M. 1995. beta-Lactamases in laboratory and clinical resistance. Clin. Microbiol. Rev. 8:557584.
61. López, E.,, M. Elez,, I. Matic, and, J. Blázquez. 2007. Antibiotic-mediated recombination: ciprofloxacin stimulates SOS-independent recombination of divergent sequences in Escherichia coli. Mol. Microbiol. 64:8393.
62. Luria, S. E., and, M. Delbrück. 1943. Mutations of bacteria from virus sensitivity to virus resistance. Genetics 28:491511.
63. Macia, M. D.,, D. Blanquer,, B. Togores,, J. Sauleda,, J. L. Pérez, and, A. Oliver. 2005. Hypermutation is a key factor in development of multiple-antimicrobial resistance in Pseudomonas aeruginosa strains causing chronic lung infections. Anti-microb. Agents Chemother. 49:33823386.
64. Maisnier-Patin, S.,, J. R. Roth,, A. Fredriksson,, T. Nystrom,, O. G. Berg, and, D. I. Andersson. 2005. Genomic buffering mitigates the effects of deleterious mutations in bacteria. Nat. Genet. 37:13761379
65. Mao, E. F.,, L. Lane,, J. Lee, and, J. H. Miller. 1997. Proliferation of mutators in a cell population. J. Bacteriol. 179:417422.
66. Matic, I.,, M. Radman,, F. Taddei,, B. Piccard,, C. Doit, et al. 1997. Highly variable mutation rates in commensal and pathogenic E. coli. Science 277:18331834.
67. Matic, I.,, C. Rayssiguier, and, M. Radman. 1995. Interspecies gene exchange in bacteria: the role of SOS and mismatch repair systems in evolution of species. Cell 80:507515.
68. Matic, I.,, F. Taddei, and, M. Radman. 2000. No genetic barriers between Salmonella enterica serovar Typhimurium and Escherichia coli in SOS-induced mismatch repair-deficent cells. J. Bacteriol. 182:59225924.
69. Medeiros, A. A. 1997. Evolution and dissemination of beta-lactamases accelerated by generations of β-lactam antibiotics. Clin. Infect. Dis. 24:S19S45.
70. Miller, K.,, A. J. O’Neill, and, I. Chopra. 2004. Escherichia coli mutators present an enhanced risk for emergence of antibiotic resistance during urinary tract infections. Antimicrob. Agents Chemother. 48:2329.
71. Modrich, P. 1991. Mechanisms and biological effects of mismatch repair. Annu. Rev. Genet. 25:229253.
72. Modrich, P., and, R. Lahue. 1996. Mismatch repair in replication fidelity, genetic recombination, and cancer biology. Annu. Rev. Biochem. 65:101133.
73. Moxon, E. R.,, P. B. Rainey,, M. A. Nowak, and, R. E. Lenski. 1994. Adaptive evolution of highly mutable loci in pathogenic bacteria. Curr. Biol. 4:2433.
74. Newcombe, H. 1949. Origin of bacterial variants. Nature 164:150151.
75. Oliver, A.,, F. Baquero, and, J. Blázquez. 2002. The mismatch repair system (mutS, mutL, and uvrD genes) in Pseudomonas aeruginosa: molecular characterization of naturally occurring mutants. Mol. Microbiol. 43:16411650.
76. Oliver, A.,, R. Cantón,, P. Campo,, F. Baquero, and, J. Blázquez. 2000. High frequency of hypermutable Pseudomonas aeruginosa in cystic fibrosis lung infection. Science 288:12511253.
77. Oliver, A.,, B. Levin,, C. Juan,, F. Baquero, and, J. Blázquez. 2004. Hypermutation and the pre-existence of antibiotic resistant Pseudomonas aeruginosa mutants: implications for susceptibility testing and treatment of chronic infections. Antimicrob. Agents Chemother. 48:42264233.
78. O’Neill, A. J., and, I. Chopra. 2002. Insertional inactivation of mutS in Staphylococcus aureus reveals potential for elevated mutation frequencies, although the prevalence of mutators in clinical isolates is low. J. Antimicrob. Chemother. 50:161169.
79. Orencia, M. C.,, J. S. Yoon,, J. E. Ness,, W. P. Stemmer, and, R. C. Stevens. 2001. Predicting the emergence of antibiotic resistance by directed evolution and structural analysis. Nat. Struct. Biol. 8:238242.
80. Pérez-Capilla, T.,, M. R. Baquero,, J. M. Gómez-Gómez,, A. Ionel,, S. Martín, and, J. Blázquez. 2005. SOS-independent induction of dinB transcription by beta-lactam-mediated inhibition of cell wall synthesis in Escherichia coli. J. Bacteriol. 187:15151518.
81. Phillips, I.,, E. Culebras,, F. Moreno, and, F. Baquero. 1987. Induction of the SOS response by new 4-quinolones. J. Antimicrob. Chemother. 20:631638.
82. Piddock, L. J. V., and, R. Wise. 1987. Induction of the SOS response in Escherichia coli by 4-quinolone antimicrobial agents. FEMS Microbiol. Lett. 41:289294.
83. Poole, K. 2001. Multidrug efflux pumps and antimicrobial resistance in P. aeruginosa and related organisms. J. Mol. Microbiol. Biotechnol. 3:225264.
84. Prudhomme, L. A.,, L. Attaiech,, G. Sanchez,, B. Martin, and, J. P. Claverys. 2006. Antibiotic stress induces genetic transformability in the human pathogen Streptococcus pneumoniae. Science 313:8992.
85. Prunier, A. L.,, B. Malbruny,, M. Laurans,, J. Brouard,, J. F. Duhamel, and, R. Leclerc. 2003. High rate of macrolide resistance in Staphylococcus aureus strains from patients with cystic fibrosis reveals high proportions of hypermutable strains. J. Infect. Dis. 187:17091716.
86. Radman, M. 1974. Phenomenology of an inducible mutagenic DNA repair pathway in Escherichia coli: SOS repair hypothesis, p. 128142. In L. Prakash,, F. Sherman,, M. Miller,, C. Lawrence, and, H. W. Tabor (ed.), Molecular and Envioronmental Aspects of Mutagenesis. Charles C. Thomas, Springfield, IL.
87. Radman, M.,, F. Taddei, and, I. Matic. 2000. Evolution-driving genes. Res. Microbiol. 151:9195.
88. Rasmaswamy, S., and, J. M. Musser. 1998. Molecular genetic basis of antimicrobial agent resistance in Mycobacterium tuberculosis: 1998 update. Tuber. Lung Dis. 79:329.
89. Rayssiguier, C.,, D. S. Thaler, and, M. Radman. 1989. The barrier to recombination between Escherichia coli and Salmonella typhimurium is disrupted in mismatch-repair mutants. Nature 342:396401.
90. Ren, L.,, M. S. Rahman, and, M. Z. Humayun. 1999. Escherichia coli cells exposed to streptomycin display a mutator phenotype J. Bacteriol. 181:10431044.
91. Richardson, A. R., and, I. Stojiljkovic. 2001. Mismatch repair and the regulation of phase variation in Neisseria meningitidis. Mol. Microbiol. 40:645655.
92. Rosche, W. A., and, P. Foster. 2000. Mutation under stress: adaptive mutation in Escherichia coli, p. 239248. In G. Storz and, R. Hengge-Aronis (ed.), Bacterial Stress Responses. ASM Press, Washington DC.
93. Rosenberg, S. M. 2001. Evolving responsively: adaptive mutation. Nat. Rev. Genet. 2:504515
94. Schaaper, R. M. 1993. Mutational specificity of two Escherichia coli dnaE antimutator alleles as determined from lacI mutation spectra. Genetics 134:10311038.
95. Shaaff, F.,, A. Reipert, and, G. Bierbaum. 2002. An elevated mutation frequency favors development of vancomycin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother. 46:35403548.
96. Sniegowski, P. D.,, P. J. Gerrish, and, R. E. Lenski. 1997. Evolution of high mutation rates in experimental populations of E. coli. Nature 387:703705.
97. Sniegowski, P. D.,, P. J. Gerrish,, T. Johnson, and, A. Shaver. 2000. The evolution of mutation rates: separating causes from consequences. Bioessays 12:10571066.
98. Spratt, B. G. 1994. Resistance to antibiotics mediated by target alterations. Science 264:388393.
99. Sutton, M. D.,, B. T. Smith,, V. G. Godoy, and, G. C. Walker. 2000. The SOS response: recent insights into umuDC-dependent mutagenesis and DNA damage tolerance. Annu. Rev. Genet. 34:479497.
100. Taddei, F.,, M. Radman,, J. Maynard-Smith,, B. Toupance,, P. H. Gouyon, and, B. Godelle. 1997. Role of mutator alleles in adaptive evolution. Nature 387:700703.
101. Tanabe, K.,, T. Kondo,, Y. Onodera, and, M. Furusawa. 1999. A conspicuous adaptability to antibiotics in the Escherichia coli mutator strain, dnaQ49. FEMS Microbiol. Lett. 176:191196.
102. Telenti, A.,, P. Imboden,, F. Marchesi,, D. Lowrie,, S. Cole,, M. M. Colston,, L. Matter,, K. Schopfer, and, T. Bodmer. 1993. Detection of rifampicin-resistance mutations in Mycobacterium tuberculosis. Lancet 341:647650.
103. Tröbner, W., and, R. Piechocki. 1984. Selection against hyper-mutability in Escherichia coli during long term evolution. Mol. Gen. Genet. 198:177178.
104. Van Rie, A. et al. 2001. Analysis for a limited number of gene codons can predict drug resistance of Mycobacterium tuberculosis in a high-incidence community. J. Clin. Microbiol. 39:636641.
105. Vulic, M.,, F. Dionisio,, F. Taddei, and, M. Radman. 1997. Molecular keys to speciation: DNA polymorphism and the control of genetic exchange in enterobacteria. Proc. Natl. Acad. Sci. USA 94:97639767.
106. Wang, H.,, J. L. Dzink-Fox,, M. Chen, and, S. B. Levy. 2001. Genetic characterization of highly fluoroquinolone-resistant clinical Escherichia coli strains from China: role of acrR mutations. Antimicrob. Agents Chemother. 45:15151521.
107. Watson, M. E.,, J. L. Burns, and, A. L. Smith. 2004. Hypermutable Haemophilus influenzae with mutations in mutS are found in cystic fibrosis sputum. Microbiology 150:29472958.
108. Ysern, P.,, B. Clerch,, M. Castaño,, I. Gilbert,, J. Barbé, and, M. Llagostera. 1990. Induction of SOS genes in Escherichia coli and mutagenesis in Salmonella typhimurium by fluoroquinolones. Mutagenesis 5:6366.

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