Evidence for Induction of Integron-Based Antibiotic Resistance by the SOS Response in a Clinical Setting

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Bacterial resistance to β-lactams may rely on acquired β-lactamases encoded by class 1 integron-borne genes. Rearrangement of integron cassette arrays is mediated by the integrase IntI1. It has been previously established that integrase expression can be activated by the SOS response in vitro, leading to speculation that this is an important clinical mechanism of acquiring resistance. Here we report the first in vivo evidence of the impact of SOS response activated by the antibiotic treatment given to a patient and its output in terms of resistance development. We identified a new mechanism of modulation of antibiotic resistance in integrons, based on the insertion of a genetic element, the gcuF1 cassette, upstream of the integron-borne cassette bla_OXA-28 encoding an extended spectrum β-lactamase. This insertion creates the fused protein GCUF1-OXA-28 and modulates the transcription, the translation, and the secretion of the β-lactamase in a Pseudomonas aeruginosa isolate (S-Pae) susceptible to the third generation cephalosporin ceftazidime. We found that the metronidazole, not an anti-pseudomonal antibiotic given to the first patient infected with S-Pae, triggered the SOS response that subsequently activated the integrase IntI1 expression. This resulted in the rearrangement of the integron gene cassette array, through excision of the gcuF1 cassette, and the full expression the β-lactamase in an isolate (R-Pae) highly resistant to ceftazidime, which further spread to other patients within our hospital. Our results demonstrate that in human hosts, the antibiotic-induced SOS response in pathogens could play a pivotal role in adaptation process of the bacteria.

Vyšlo v časopise: Evidence for Induction of Integron-Based Antibiotic Resistance by the SOS Response in a Clinical Setting. PLoS Pathog 8(6): e32767. doi:10.1371/journal.ppat.1002778
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002778

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Zdroje

1. PartridgeSRTsafnatGCoieraEIredellJR 2009 Gene cassettes and cassette arrays in mobile resistance integrons. FEMS Microbiol Rev 33 757 784

2. CollisCMHallRM 1992 Gene cassettes from the insert region of integrons are excised as covalently closed circles. Mol Microbiol 6 2875 2885

3. CambrayGGueroutAMMazelD 2010 Integrons. Annu Rev Genet 44 141 166

4. JovéTDa RéSDenisFMazelDPloyMC 2010 Inverse correlation between promoter strength and excision activity in class 1 integrons. PLoS Genet 6 e1000793

5. CoyneSGuigonGCourvalinPPérichonB 2010 Screening and quantification of the expression of antibiotic resistance genes in Acinetobacter baumannii with a microarray. Antimicrob Agents Chemother 54 333 340

6. JacquierHZaouiCSanson-le PorsM-JMazelDBerçotB 2009 Translation regulation of integrons gene cassette expression by the attC sites. Mol Microbiol 72 1475 1486

7. ErillICampoySBarbeJ 2007 Aeons of distress: an evolutionary perspective on the bacterial SOS response. FEMS Microbiol Rev 31 637 656

8. GuerinECambrayGSanchez-AlberolaNCampoySErillI 2009 The SOS response controls integron recombination. Science 324 1034

9. CambrayGSanchez-AlberolaNCampoySGuerinEDa ReS 2011 Prevalence of SOS-mediated control of integron integrase expression as an adaptive trait of chromosomal and mobile integrons. Mobile DNA 2 6

10. BaharogluZBikardDMazelD 2010 Conjugative DNA transfer induces the bacterial SOS response and promotes antibiotic resistance development through integron activation. PLoS Genet 6 e1001165

11. BaharogluZMazelD 2011 Vibrio cholerae triggers SOS and mutagenesis in response to a wide range of antibiotics: a route towards multiresistance. Antimicrob Agents Chemother 55 2438 2441

12. BlazquezJGomez-GomezJMOliverAJuanCKapurV 2006 PBP3 inhibition elicits adaptive responses in Pseudomonas aeruginosa. Mol Microbiol 62 84 99

13. MillerCThomsenLEGaggeroCMosseriRIngmerH 2004 SOS response induction by β-lactams and bacterial defense against antibiotic lethality. Science 305 1629 1631

14. HocquetDDehecqBBertrandXPlésiatP 2011 A strain-tailored double-disc synergy test detects extended-spectrum oxacillinases in Pseudomonas aeruginosa. J Clin Microbiol 49 2262 2265

15. HocquetDPlésiatPDehecqBMariottePTalonD 2010 Nationwide investigation of extended-spectrum β-lactamases, metallo-β-lactamases, and extended-spectrum oxacillinases produced by ceftazidime-resistant Pseudomonas aeruginosa strains in France. Antimicrob Agents Chemother 54 3512 3515

16. BertFBrangerCLambert-ZechovskyN 2002 Identification of PSE and OXA β-lactamase genes in Pseudomonas aeruginosa using PCR-restriction fragment length polymorphism. J Antimicrob Chemother 50 11 18

17. FluitACSchmitzFJ 2004 Resistance integrons and super-integrons. Clin Microbiol Infect 10 272 288

18. GalimandMLambertTGerbaudGCourvalinP 1993 Characterization of the aac(6′)-Ib gene encoding an aminoglycoside 6′-N-acetyltransferase in Pseudomonas aeruginosa BM2656. Antimicrob Agents Chemother 37 1456 1462

19. PoirelLGirlichDNaasTNordmannP 2001 OXA-28, an extended-spectrum variant of OXA-10 β-lactamase from Pseudomonas aeruginosa and its plasmid- and integron-located gene. Antimicrob Agents Chemother 45 447 453

20. KoshlandDBotsteinD 1980 Secretion of β-lactamase requires the carboxy end of the protein. Cell 20 749 760

21. O'DonnellSMJanssenGR 2001 The initiation codon affects ribosome binding and translational efficiency in Escherichia coli of cI mRNA with or without the 5′ untranslated leader. J Bacteriol 183 1277 1283

22. ShineJDalgarnoL 1974 The 3′-terminal sequence of Escherichia coli 16S ribosomal RNA: complementarity to nonsense triplets and ribosome binding sites. Proc Natl Acad Sci U S A 71 1342 1346

23. SalisHMMirskyEAVoigtCA 2009 Automated design of synthetic ribosome binding sites to control protein expression. Nat Biotechnol 27 946 950

24. QuillardetPHofnungM 1993 The SOS chromotest: a review. Mutat Res 297 235 279

25. GuérinEJovéTTabesseAMazelDPloyM-C 2011 High-level Gene cassette transcription prevents integrase expression in class 1 integrons. J Bacteriol 193 5675 5682

26. DeanaABelascoJG 2005 Lost in translation: the influence of ribosomes on bacterial mRNA decay. Gene Dev 19 2526 2533

27. KuhnA 1987 Bacteriophage M13 procoat protein inserts into the plasma membrane as a loop structure. Science 238 1413 1415

28. BouvierMDucos-GalandMLootCBikardDMazelD 2009 Structural features of single-stranded integron cassette attC sites and their role in strand selection. PLoS Genet 5 e1000632

29. FrumerieCDucos-GalandMGopaulDNMazelD 2010 The relaxed requirements of the integron cleavage site allow predictable changes in integron target specificity. Nucleic Acids Res 38 559 569

30. Cipriano SouzaRVicenteACVieiraVVMarquesSGSoaresMdGA 2008 Clindamycin and metronidazole as independent risk factors for nosocomial acquisition of multidrug-resistant Pseudomonas aeruginosa. J Hosp Infect 69 402 403

31. LöfmarkSEdlundCNordCE 2010 Metronidazole is still the drug of choice for treatment of anaerobic infections. Clin Infect Dis 50 S16 S23

32. SissonGJeongJ-YGoodwinABrydenLRosslerN 2000 Metronidazole activation is mutagenic and causes DNA fragmentation in Helicobacter pylori and in Escherichia coli containing a cloned H. pylori rdxA+ (nitroreductase) gene. J Bacteriol 182 5091 5096

33. TocherJHEdwardsDI 1994 Evidence for the direct interaction of reduced metronidazole derivatives with DNA bases. Biochem Pharmacol 48 1089 1094

34. MenéndezDRojasEHerreraLALópezMCSordoM 2001 DNA breakage due to metronidazole treatment. Mutat Res 478 153 158

35. LivermoreDM 2002 Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis 34 634 640

36. DepardieuFPodglajenILeclercqRCollatzECourvalinP 2007 Modes and modulations of antibiotic resistance gene expression. Clin Microbiol Rev 20 79 114

37. FoucaultMLDepardieuFCourvalinPGrillot-CourvalinC 2010 Inducible expression eliminates the fitness cost of vancomycin resistance in enterococci. Proc Natl Acad Sci U S A 107 16964 16969

38. AnderssonDIHughesD 2010 Antibiotic resistance and its cost: is it possible to reverse resistance? Nat Rev Microbiol 8 260 271

39. LuTKCollinsJJ 2009 Engineered bacteriophage targeting gene networks as adjuvants for antibiotic therapy. Proc Natl Acad Sci U S A 106 4629 4634

40. CirzRTChinJKAndesDRde Crécy-LagardVCraigWA 2005 Inhibition of mutation and combating the evolution of antibiotic resistance. PLoS Biol 3 e176

41. ClineDJHoltSLSingletonSF 2007 Inhibition of Escherichia coli RecA by rationally redesigned N-terminal helix. Org Biomolec Chem 5 1525 1528

42. SextonJZWigleTJHeQHughesMASmithGR 2010 Novel inhibitors of Escherichia coli RecA ATPase activity. Curr Chem Genomics 4 34 42

43. WigleTJSextonJZGromovaAVHadimaniMBHughesMA 2009 Inhibitors of RecA activity discovered by high-throughput screening: cell-permeable small molecules attenuate the SOS response in Escherichia coli. J Biomol Screen 14 1092 1101

44. TalonDCailleauxVThouverezMMichel-BriandY 1996 Discriminatory power and usefulness of pulsed-field gel electrophoresis in epidemiological studies of Pseudomonas aeruginosa. J Hosp Infect 32 135 145

45. CLSI 2009 Method for dilution antimicrobial susceptibility tests for bacteria that grow aerobically. Approved standard — eighth edition, CLSI document M7-A7

46. DumasJ-Lvan DeldenCPerronKKöhlerT 2006 Analysis of antibiotic resistance gene expression in Pseudomonas aeruginosa by quantitative real-time-PCR. FEMS Microbiol Lett 254 217 225

47. ChoiKHSchweizerHP 2005 An improved method for rapid generation of unmarked Pseudomonas aeruginosa deletion mutants. BMC Microbiol 5 30

48. SchweizerHP 1992 Allelic exchange in Pseudomonas aeruginosa using novel ColE1-type vectors and a family of cassettes containing a portable oriT and the counter-selectable Bacillus subtilis sacB marker. Mol Microbiol 6 1195 1204

49. DilgerKFuxRRöckDMörikeKGleiterCH 2007 Effect of high-dose metronidazole on pharmacokinetics of oral budesonide and vice versa: a double drug interaction study. J Clin Pharmacol 47 1532 1539