The mutational landscape of quinolone resistance in Escherichia coli

Autoři: Kamya Bhatnagar aff001;  Alex Wong aff001
Působiště autorů: Department of Biology, Carleton University, Ottawa, ON, Canada aff001
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224650


The evolution of antibiotic resistance is influenced by a variety of factors, including the availability of resistance mutations, and the pleiotropic effects of such mutations. Here, we isolate and characterize chromosomal quinolone resistance mutations in E. coli, in order to gain a systematic understanding of the rate and consequences of resistance to this important class of drugs. We isolated over fifty spontaneous resistance mutants on nalidixic acid, ciprofloxacin, and levofloxacin. This set of mutants includes known resistance mutations in gyrA, gyrB, and marR, as well as two novel gyrB mutations. We find that, for most mutations, resistance tends to be higher to nalidixic acid than relative to the other two drugs. Resistance mutations had deleterious impacts on one or more growth parameters, suggesting that quinolone resistance mutations are generally costly. Our findings suggest that the prevalence of specific gyrA alleles amongst clinical isolates are driven by high levels of resistance, at no more cost than other resistance alleles.

Klíčová slova:

Antibiotic resistance – Antibiotics – Antimicrobial resistance – Escherichia coli – Mutation – Mutation detection – Natural selection – Point mutation


1. Public health agency of Canada (PHAC). (2015–2016). Available from:

2. Canadian antimicrobial resistance alliance (CARA). CANWARD susceptibility report. 2015. Available

3. Piddock LJ. The crisis of no new antibiotics—what is the way forward? Lancet Infect Dis. 2012;12(3):249–253. doi: 10.1016/S1473-3099(11)70316-4 22101066

4. Bartlett JG, Gilbert DN, Spellberg B. Seven ways to preserve the miracle of antibiotics. Clin Infect Dis. 2013;56(10):1445–1450. doi: 10.1093/cid/cit070 23403172

5. Gross M. Antibiotics in crisis. Curr Biol. 2013;23(24):1063–1065.

6. Gould IM, Bal AM. New antibiotic agents in the pipeline and how they can overcome microbial resistance. Virulence. 2013;4(2):185–191. doi: 10.4161/viru.22507 23302792

7. Viswanathan VK. Off-label abuse of antibiotics by bacteria. Gut Microbes. 2014;5(1):3–4. doi: 10.4161/gmic.28027 24637595

8. Gerrish PJ, Lenski RE. The fate of competing beneficial mutations in an asexual population. Genetica. 1998;102–103(1–6):127–144.

9. Wilke CO. The speed of adaptation in large asexual populations. Genetics. 2004;167(4):2045–2053. doi: 10.1534/genetics.104.027136 15342539

10. Toprak E, Veres A, Michel J, Chait R, Hartl D, Kishony R. Evolutionary paths to antibiotic resistance under dynamically sustained drug selection. Nat Genet. 2011;44(1):101–105. doi: 10.1038/ng.1034 22179135

11. Winkler J, Kao KC. Harnessing recombination to speed adaptive evolution in Escherichia coli. Metab Eng. 2012;14(5):487–495. doi: 10.1016/j.ymben.2012.07.004 22842472

12. Alekshun MN, Kim YS, Levy SB. Mutational analysis of MarR, the negative regulator of marRAB expression in Escherichia coli, suggests the presence of two regions required for DNA binding. Mol Microbiol. 2000;35(6):1394–1404. doi: 10.1046/j.1365-2958.2000.01802.x 10760140

13. Ruiz J. Mechanisms of resistance to quinolones: target alterations, decreased accumulation and DNA gyrase protection. J Antimicrob Chemother. 2003;51(5):1109–1117. doi: 10.1093/jac/dkg222 12697644

14. Hooper DC. Bacterial resistance to fluoroquinolones: mechanisms and patterns. Adv Exp Med Biol. 1995;390:49–57. doi: 10.1007/978-1-4757-9203-4_4 8718601

15. Andersson DI, Levin BR. The biological cost of antibiotic resistance. Curr Opin Microbiol. 1999;2(5):489–493. 10508723

16. Andersson MI, MacGowan AP. Development of the quinolones. J Antimicrob Chemother. 2003;51(suppl 1):1–11.

17. Pál C, Papp B, Lázár V. Collateral sensitivity of antibiotic-resistant microbes. Trends Microbiol. 2015;23(7):401–407. doi: 10.1016/j.tim.2015.02.009 25818802

18. Vogwill T, MacLean RC. The genetic basis of the fitness costs of antimicrobial resistance: a meta-analysis approach. Evol Appl. 2015;8(3):284–295. doi: 10.1111/eva.12202 25861386

19. Hall AR, Iles JC, MacLean RC. The fitness cost of rifampicin resistance in Pseudomonas aeruginosa depends on demand for RNA polymerase. Genetics. 2011;187(3):817–822. doi: 10.1534/genetics.110.124628 21220359

20. Hall BG, Acar H, Nandipati A, Barlow M. Growth rates made easy. Mol Biol Evol. 2014;31(1):232–238. doi: 10.1093/molbev/mst187 24170494

21. Tenover FC. Mechanisms of antimicrobial resistance in bacteria. Am J Infect Control. 2006;34(5 Suppl 1):S3–S10.

22. Reynolds MG. Compensatory evolution in rifampin-resistant Escherichia coli. Genetics. 2000;156(4):1471–1481. 11102350

23. Levin BR, Perrot V, Walker N. Compensatory mutations, antibiotic resistance and the population genetics of adaptive evolution in bacteria. Genetics. 2000;154(3):985–997. 10757748

24. Lindgren PK, Karlsson A, Hughes D. Mutation rate and evolution of fluoroquinolone resistance in Escherichia coli isolates from patients with urinary tract infections. Antimicrob Agents Chemother. 2003;47(10):3222–3232. doi: 10.1128/AAC.47.10.3222-3232.2003 14506034

25. Luo N, Pereira S, Sahin O, Lin J, Huang S, Michel L, Zhang Q. Enhanced in vivo fitness of fluoroquinolone-resistant Campylobacter jejuni in the absence of antibiotic selection pressure. Proc Nat Acad Sci of the U S A. 2005;102(3):541–546.

26. Rozen DE, McGee L, Levin BR, Klugman KP. Fitness costs of fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother. 2007;51(2):412–416. doi: 10.1128/AAC.01161-06 17116668

27. Zhang Q, Sahin O, McDermott PF, Payot S. Fitness of antimicrobial-resistant Campylobacter and Salmonella. Microbes Infect. 2006;8(7):1972–1978. doi: 10.1016/j.micinf.2005.12.031 16714138

28. Melnyk AH, Wong A, Kassen R. The fitness costs of antibiotic resistance mutations. Evol Appl. 2015;8(3):273–283. doi: 10.1111/eva.12196 25861385

29. Horowitz DS, Wang JC. Mapping the active site tyrosine of Escherichia coli DNA gyrase. J Biol Chem. 1987;262(11):5339–5344. 3031051

30. Yoshida H, Bogaki M, Nakamura S, Ubukata K, Konno M. Nucleotide sequence and characterization of the Staphylococcus aureus norA gene, which confers resistance to quinolones. J Bacteriol. 1990;172(12):6942–6949. doi: 10.1128/jb.172.12.6942-6949.1990 2174864

31. Hooper DC. Mechanisms of quinolone resistance. Drug Resist Updat. 1999;2(1):38–55. doi: 10.1054/drup.1998.0068 11504468

32. Sullivan EA, Kreiswirth BN, Palumbo L, Kapur V, Musser JM, Ebrahimzadeh A, et al. Emergence of fluoroquinolone- resistant tuberculosis in New York City. Lancet. 1995;345(8958):1148–1150. doi: 10.1016/s0140-6736(95)90980-x 7723548

33. Lu T, Zhao X, Drlica K. Gatifloxacin activity against quinolone-resistant gyrase: allele-specific enhancement of bacteriostatic and bactericidal activity by the C-8-methoxy group. Antimicrob Agents Chemother. 1999;43(12):2969–2974. 10582891

34. Friedman SM, Lu T, Drlica K. Mutation in the DNA gyrase A gene of Escherichia coli that expands the quinolone resistance-determining region. Antimicrob Agents Chemother. 2001;45(8):2378–2380. doi: 10.1128/AAC.45.8.2378-2380.2001 11451702

35. Yoshida H, Bogaki M, Nakamura M, Yamanaka LM, Nakamura S. Quinolone resistance-determining region in the DNA gyrase gyrB gene of Escherichia coli. Antimicrob Agents Chemother. 1991;35(8):1647–1650. doi: 10.1128/aac.35.8.1647 1656869

36. Heddle J, Maxwell A. Quinolone-binding pocket of DNA gyrase: Role of GyrB. Antimicrob Agents Chemother. 2002;46(6):1805–1815. doi: 10.1128/AAC.46.6.1805-1815.2002 12019094

37. Weigel LM, Anderson GJ, Tenover FC. DNA gyrase and topoisomerase IV mutations associated with fluoroquinolone resistance in Proteus mirabilis. Antimicrob Agents Chemother. 2002;46(8):2582–2587. doi: 10.1128/AAC.46.8.2582-2587.2002 12121936

38. Alekshun MN, Levy SB. Alteration of the repressor activity of MarR, the negative regulator of the Escherichia coli mar locus, by multiple chemicals in vitro. J Bacteriol. 1999a;181(15):4669–4672.

39. Alekshun MN, Levy SB. Characterization of MarR superrepressor mutants. J Bacteriol. 1999b;181(10):3303–3306.

40. Cohen SP, Hächler H, Levy SB. Genetic and functional analysis of the multiple antibiotic resistance (mar) locus in Escherichia coli. J Bacteriol. 1993;175(5):1484–1492. doi: 10.1128/jb.175.5.1484-1492.1993 8383113

41. Alekshun MN, Levy SB. Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulon. Antimicrob Agents Chemother. 1997;41(10):2067–2075. 9333027

42. Alekshun MN, Levy SB, Mealy TR, Seaton BA, Head JF. The crystal structure of MarR, a regulator of multiple antibiotic resistance, at 2.3 Å resolution. Nat Struct Biol. 2001;8(8):710–714. doi: 10.1038/90429 11473263

43. Randall LP, Woodward MJ. The multiple antibiotic resistance (mar) locus and its significance. Res Vet Sci. 2002;72(2):87–93. doi: 10.1053/rvsc.2001.0537 12027588

44. Imamovic L, Sommer MO. Use of collateral sensitivity networks to design drug cycling protocols that avoid resistance development. Sci Transl Med. 2013;5(204):204ra132. 24068739

45. Lázár V, Pal Singh G, Spohn R, et al. Bacterial evolution of antibiotic hypersensitivity. Mol Syst Biol. 2013;9:700. 24169403

46. Luria SE, Delbrück M. Mutations of bacteria from virus sensitivity to virus resistance. Genetics. 1943;28(6):491–511. 17247100

47. Foster PL. Methods for determining spontaneous mutation rates. Methods Enzymol. 2006;409:195–213. doi: 10.1016/S0076-6879(05)09012-9 16793403

48. Ma WT, Sandri GH, Sarkar S. Analysis of the Luria-Delbrück distribution using discrete convolution powers. J Appl Probab. 1992;29(2):255–267.

49. Sarkar S, Ma WT, Sandri GH. On fluctuation analysis: a new, simple and efficient method for computing the expected number of mutants. Genetica. 1992;85(2):173–179. doi: 10.1007/bf00120324 1624139

50. Hall BM, Ma CX, Liang P, Singh KK. Fluctuation analysis CalculatOR: a web tool for the determination of mutation rate using Luria- Delbrück fluctuation analysis. Bioinformatics. 2009;25(12):1564–1565. doi: 10.1093/bioinformatics/btp253 19369502

51. Rosche WA, Foster PL. Determining mutation rates in bacterial populations. Methods. 2000;20(1):4–17. doi: 10.1006/meth.1999.0901 10610800

52. Zheng Q. Progress of a half century in the study of the Luria–Delbrück distribution. Math Biosci. 1999;162(1–2):1–32. doi: 10.1016/s0025-5564(99)00045-0 10616278

53. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–2120. doi: 10.1093/bioinformatics/btu170 24695404

54. Langmead B, Trapnell C, Pop M, Salzberg SL. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009;10(3):R25–R25. doi: 10.1186/gb-2009-10-3-r25 19261174

55. Li H, Handsaker B, Wysoker A, Fennell T, Ruan J, Homer N, Marth G, Abecasis G, Durbin R. The Sequence Alignment/Map format and SAMtools. Bioinformatics. 2009;25(16):2078–2079. doi: 10.1093/bioinformatics/btp352 19505943

56. Cingolani P, Wang le L, Coon M, Nguyen T, Wang L, Land SJ, et al. A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3. Fly. 2012;6(2):80–92. doi: 10.4161/fly.19695 22728672

57. Yoshida H, Bogaki M, Nakamura M, Nakamura S. Quinolone resistance-determining region in the DNA gyrase gyrA gene of Escherichia coli. Antimicrob Agents Chemother. 1990;34(6):1271–1272. doi: 10.1128/aac.34.6.1271 2168148

58. Heisig P, Tschorny R. Characterization of fluoroquinolone-resistant mutants of Escherichia coli selected in vitro. Antimicrob Agents Chemother. 1994;38(6):1284–1291. doi: 10.1128/aac.38.6.1284 8092826

59. Hopkins KL, Davies RH, Threlfall EJ. Mechanisms of quinolone resistance in Escherichia coli and Salmonella: recent developments. Int J Antimicrob Agents. 2005;25(5):358–373. doi: 10.1016/j.ijantimicag.2005.02.006 15848289

60. Oram M, Fisher LM. 4-Quinolone resistance mutations in the DNA gyrase of Escherichia coli clinical isolates identified by using the polymerase chain reaction. Antimicrob Agents Chemother. 1991;35(2):387–389. doi: 10.1128/aac.35.2.387 1850972

61. Maxwell A. The molecular basis of quinolone action. J Antimicrob Chemother. 1992;30(4):409–414. doi: 10.1093/jac/30.4.409 1337067

62. Everett MJ, Jin YF, Ricci V, Piddock LJ. Contributions of individual mechanisms to fluoroquinolone resistance in 36 Escherichia coli strains isolated from humans and animals. Antimicrob Agents Chemother. 1996;40(10):2380–2386. 8891148

63. Heisig P. Genetic evidence for a role of parC mutations in development of high-level fluoroquinolone resistance in Escherichia coli. Antimicrob Agents Chemother. 1996;40(4):879–885. 8849244

64. Lindgren PK, Marcusson LL, Sandvang D, Frimodt-Møller N, Hughes D. Biological cost of single and multiple norfloxacin resistance mutations in Escherichia coli implicated in urinary tract infections. Antimicrob Agents Chemother. 2005;49(6):2343–2351. doi: 10.1128/AAC.49.6.2343-2351.2005 15917531

65. Moon DC, Seol SY, Gurung M, Jin JS, Choi CH, Kim J, et al. Emergence of a new mutation and its accumulation in the topoisomerase IV gene confers high levels of resistance to fluoroquinolones in Escherichia coli isolates, Int J of Antimicrob Agents. 2010;35(1):76–79.

66. Marcusson LL, Frimodt-Møller N, Hughes D. Interplay in the selection of fluoroquinolone resistance and bacterial fitness. PLoS Pathog. 2009;5(8):e1000541. doi: 10.1371/journal.ppat.1000541 19662169

67. Hallett P, Maxwell A. Novel quinolone resistance mutations of the Escherichia coli DNA gyrase A protein: enzymatic analysis of the mutant proteins. Antimicrob Agents Chemother. 1991;35(2):335–340. doi: 10.1128/aac.35.2.335 1850970

68. Reece R, Maxwell A. DNA gyrase: structure and function. Crit Rev Biochem Mol Biol. 1991;26(3–4):335–375. doi: 10.3109/10409239109114072 1657531

69. Brino L, Urzhumtsev A, Mousli M, Bronner C, Mitschler A, Oudet P, et al. Dimerization of Escherichia coli DNA-gyrase B provides a structural mechanism for activating the ATPase catalytic center. J Biol Chem. 2000;275(13):9468–9475. doi: 10.1074/jbc.275.13.9468 10734094

70. Nakamura S, Nakamura M, Kojima T, Yoshida H. gyrA and gyrB mutations in quinolone-resistant strains of Escherichia coli. Antimicrob Agents Chemother. 1989;33(2):254–255. doi: 10.1128/aac.33.2.254 2655532

71. Vila J, Ruiz J, Goñi P, De Anta MT. Detection of mutations in parC in quinolone-resistant clinical isolates of Escherichia coli. Antimicrob Agents Chemother. 1996;40(2):491–493. 8834907

72. Gensberg K, Jin YF, Piddock LJ. A novel gyrB mutation in a fluoroquinolone-resistant clinical isolate of Salmonella typhimurium. FEMS Microbiol Lett. 1995;132(1–2):57–60. doi: 10.1111/j.1574-6968.1995.tb07810.x 7590165

73. Stanger FV, Dehio C, Schirmer T. Structure of the N-terminal gyrase B fragment in complex with ADPPi reveals rigid-body motion induced by ATP hydrolysis. PLoS One. 2014;9(9):e107289. doi: 10.1371/journal.pone.0107289 25202966

74. Sulavik MC, Gambino LF, Miller PF. The MarR repressor of the multiple antibiotic resistance (mar) operon in Escherichia coli: prototypic member of a family of bacterial regulatory proteins involved in sensing phenolic compounds. Mol Med. 1995;1(4):436–446. 8521301

75. Finn RD, Coggill P, Eberhardt RY, et al. The Pfam protein families database: towards a more sustainable future. Nucleic Acids Res. 2016;44(D1):D279–D285. doi: 10.1093/nar/gkv1344 26673716

76. UniProt Consortium, T. UniProt: the universal protein knowledgebase. Nuc Acids Res. 2018;45(D1):D158–D169.

77. Kampranis SC, Bates AD, Maxwell A. A model for the mechanism of strand passage by DNA gyrase. Proc Natl Acad Sci U S A. 1999;96(15):8414–8419. doi: 10.1073/pnas.96.15.8414 10411889

78. Champoux JJ. DNA topoisomerases: Structure, function, and mechanism. Annu Rev Biochem. 2001;70:369–413. doi: 10.1146/annurev.biochem.70.1.369 11395412

79. Sissi C, Palumbo M. In front of and behind the replication fork: bacterial type IIA topoisomerases. Cell Mol Life Sci. 2010;67(12):2001–2024. doi: 10.1007/s00018-010-0299-5 20165898

80. Gubaev A, Klostermeier D. The mechanism of negative DNA supercoiling: a cascade of DNA-induced conformational changes prepares gyrase for strand passage. DNA Repair. 2014;16:23–34. doi: 10.1016/j.dnarep.2014.01.011 24674625

81. Domagala JM. Structure-activity and structure side effect relationships for the quinolone antibacterials. J Antimicrob Chemother. 1994;33(4):685–706. doi: 10.1093/jac/33.4.685 8056688

82. Tillotson GS. Quinolones: structure-activity relationships and future predictions. J Med Microbiol. 1996;44(5):320–324. doi: 10.1099/00222615-44-5-320 8636945

83. Zhao X, Wang JY, Xu C, Dong Y, Zhou J, Domagala J, Drlica K. Killing of Staphylococcus aureus by C-8-methoxy fluoroquinolones. Antimicrob Agents Chemother. 1998;42(4):956–958. 9559820

84. Zhao X, Drlica K. Restricting the selection of antibiotic-resistant mutants: a general strategy derived from fluoroquinolone studies. Clin Infect Dis. 2001;33(Suppl 3):S147–S156.

85. Fukuda H, Hiramatsu K. Primary targets of fluoroquinolones in Streptococcus pneumoniae. Antimicrob Agents Chemother. 1999;43(2):410–412. 9925547

86. Jorgensen JH, Weigel LM, Ferraro MJ, Swenson JM, Tenover FC. Activities of newer fluoroquinolones against Streptococcus pneumoniae clinical isolates including those with mutations in the gyrA, parC, and parE loci. Antimicrob Agents Chemother. 1999;43(2):329–334. 9925527

87. Dong Y, Zhao X, Domagala J, Drlica K. Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus. Antimicrob Agents Chemother. 1999;43(7):1756–1758. 10390236

88. Pestova E, Millichap JJ, Noskin GA, Peterson LR. Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones. J Antimicrob Chemother. 2000;45(5):583–590. doi: 10.1093/jac/45.5.583 10797078

89. Sanders CC. Mechanisms responsible for cross-resistance and dichotomous resistance among the quinolones. Clin Infect Dis. 2001;32(Suppl 1):S1–S8.

90. Peterson LR. Quinolone molecular structure-activity relationships: what we have learned about improving antimicrobial activity. Clin Infect Dis. 2001;33(Suppl 3):S180–S186.

91. Michot JM, Seral C, Van Bambeke F, Mingeot-Leclercq MP, Tulkens PM. Influence of efflux transporters on the accumulation and efflux of four quinolones (ciprofloxacin, levofloxacin, garenoxacin, and moxifloxacin) in J774 macrophages. Antimicrob Agents Chemother. 2005;49(6):2429–2437. doi: 10.1128/AAC.49.6.2429-2437.2005 15917543

92. Barnard FM, Maxwell A. Interaction between DNA gyrase and quinolones: Effects of alanine mutations at GyrA subunit residues Ser83 and Asp87. Antimicrob Agents Chemother. 2001;45(7):1994–2000. doi: 10.1128/AAC.45.7.1994-2000.2001 11408214

93. Morgan-Linnell SK, Zechiedrich L. Contributions of the combined effects of topoisomerase mutations toward fluoroquinolone resistance in Escherichia coli. Antimicrob Agents Chemother. 2007;51(11):4205–4208. doi: 10.1128/AAC.00647-07 17682104

94. Morgan-Linnell SK, Becnel Boyd L, Steffen D, Zechiedrich L. Mechanisms accounting for fluoroquinolone resistance in Escherichia coli clinical isolates. Antimicrob Agents Chemother. 2008;53(1):235–241. doi: 10.1128/AAC.00665-08 18838592

95. Becnel Boyd L, Maynard MJ, Morgan-Linnell SK, et al. Relationships among ciprofloxacin, gatifloxacin, levofloxacin, and norfloxacin MICs for fluoroquinolone-resistant Escherichia coli clinical isolates. Antimicrob Agents Chemother. 2009;53(1):229–234. doi: 10.1128/AAC.00722-08 18838594

96. Azéma J, Guidetti B, Korolyov A, Kiss R, Roques C, Constant P, et al. Synthesis of lipophilic dimeric -7/-7-linked ciprofloxacin and -6/-6-linked levofloxacin derivatives. Versatile biological evaluations of monomeric and dimeric fluoroquinolone derivatives as potential antitumor, antibacterial or antimycobacterial agents. Euro J of Medicinal Chem. 2011;46(12):6025–6038.

97. Björkman J, Nagaev I, Berg OG, Hughes D, Andersson DI. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science. 2000;287(5457):1479–1482. doi: 10.1126/science.287.5457.1479 10688795

98. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, Bohannan BJ. The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science. 2006;312(5782):1944–1946. doi: 10.1126/science.1124410 16809538

99. Andersson DI, Hughes D. Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Micro. 2010;8(4):260–271.

100. Bagel S, Hüllen V, Wiedemann B, Heisig P. Impact of gyrA and parC mutations on quinolone resistance, doubling time, and supercoiling degree of Escherichia coli. Antimicrob Agents Chemother. 1999;43(4):868–875. 10103193

101. Kugelberg E, Löfmark S, Wretlind B, Andersson DI. Reduction of the fitness burden of quinolone resistance in Pseudomonas aeruginosa. J Antimicrob Chemother. 2005;55(1):22–30. doi: 10.1093/jac/dkh505 15574475

102. MacLean RC, Vogwill T. Limits to compensatory adaptation and the persistence of antibiotic resistance in pathogenic bacteria. Evol Med Public Health. 2014;2015(1):4–12. doi: 10.1093/emph/eou032 25535278

103. Betitra Y, Teresa V, Miguel V, Abdelaziz T. Determinants of quinolone resistance in Escherichia coli causing community-acquired urinary tract infection in Bejaia, Algeria. Asian Pac J Trop Med. (2014);7(6):462–467. doi: 10.1016/S1995-7645(14)60075-4 25066395

104. Basra P, Alsaadi A, Bernal-Astrain G, et al. Fitness tradeoffs of antibiotic resistance in extraintestinal pathogenic Escherichia coli. Genome Biol Evol. 2018;10(2):667–679. doi: 10.1093/gbe/evy030 29432584

105. Wong A, Rodrigue N, Kassen R. Genomics of adaptation during experimental evolution of the opportunistic pathogen Pseudomonas aeruginosa. PLoS Genet. 2012;8(9):e1002928. doi: 10.1371/journal.pgen.1002928 23028345

Článek vyšel v časopise


2019 Číslo 11