Compensatory Evolution of Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in

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The prevalence of antibiotic resistance genes in pathogenic bacteria is a major challenge to treating many infectious diseases. The spread of these genes is driven by the strong selection imposed by the use of antibacterial drugs. However, in the absence of drug selection, antibiotic resistance genes impose a fitness cost, which can be ameliorated by compensatory mutations. In Streptococcus pneumoniae, β-lactam resistance is caused by mutations in three penicillin-binding proteins, PBP1a, PBP2x, and PBP2b, all of which are implicated in cell wall synthesis and the cell division cycle. We found that the fitness cost and cell division defects conferred by pbp2b mutations (as determined by fitness competitive assays in vitro and in vivo and fluorescence microscopy) were fully compensated by the acquisition of pbp2x and pbp1a mutations, apparently by means of an increased stability and a consequent mislocalization of these protein mutants. Thus, these compensatory combinations of pbp mutant alleles resulted in an increase in the level and spectrum of β-lactam resistance. This report describes a direct correlation between antibiotic resistance increase and fitness cost compensation, both caused by the same gene mutations acquired by horizontal transfer. The clinical origin of the pbp mutations suggests that this intergenic compensatory process is involved in the persistence of β-lactam resistance among circulating strains. We propose that this compensatory mechanism is relevant for β-lactam resistance evolution in Streptococcus pneumoniae.

Vyšlo v časopise: Compensatory Evolution of Mutations Restores the Fitness Cost Imposed by β-Lactam Resistance in. PLoS Pathog 7(2): e32767. doi:10.1371/journal.ppat.1002000
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1002000

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Zdroje

1. JacobsMR 2008 Antimicrobial-resistant Streptococcus pneumoniae: trends and management. Expert Rev Anti Infect Ther 6 619 635

2. ZapunAContreras-MartelCVernetT 2008 Penicillin-binding proteins and beta-lactam resistance. FEMS Microbiol Rev 32 361 385

3. ClaverysJPPrudhommeMMartinB 2006 Induction of competence regulons as a general response to stress in gram-positive bacteria. Annu Rev Microbiol 60 451 475

4. MacheboeufPContreras-MartelCJobVDidebergODessenA 2006 Penicillin binding proteins: key players in bacterial cell cycle and drug resistance processes. FEMS Microbiol Rev 30 673 691

5. Maisnier-PatinSAnderssonDI 2004 Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution. Res Microbiol 155 360 369

6. AnderssonDI 2006 The biological cost of mutational antibiotic resistance: any practical conclusions? Curr Opin Microbiol 9 461 465

7. BalsalobreLde la CampaAG 2008 Fitness of Streptococcus pneumoniae fluoroquinolone-resistant strains with topoisomerase IV recombinant genes. Antimicrob Agents Chemother 52 822 830

8. RozenDEMcGeeLLevinBRKlugmanKP 2007 Fitness costs of fluoroquinolone resistance in Streptococcus pneumoniae. Antimicrob Agents Chemother 51 412 416

9. BrilesDECrainMJGrayBMFormanCYotherJ 1992 Strong association between capsular type and virulence for mice among human isolates of Streptococcus pneumoniae. Infect Immun 60 111 116

10. Azoulay-DupuisERieuxVMuffat-JolyMBedosJPValleeE 2000 Relationship between capsular type, penicillin susceptibility, and virulence of human Streptococcus pneumoniae isolates in mice. Antimicrob Agents Chemother 44 1575 1577

11. RieuxVCarbonCAzoulay-DupuisE 2001 Complex relationship between acquisition of beta-lactam resistance and loss of virulence in Streptococcus pneumoniae. J Infect Dis 184 66 72

12. TrzcinskiKThompsonCMGilbeyAMDowsonCGLipsitchM 2006 Incremental increase in fitness cost with increased beta -lactam resistance in pneumococci evaluated by competition in an infant rat nasal colonization model. J Infect Dis 193 1296 1303

13. Albarracin OrioAGCortesPRTregnaghiMPinasGEEcheniqueJR 2008 A new serotype 14 variant of the pneumococcal Spain9V-3 international clone detected in the central region of Argentina. J Med Microbiol 57 992 999

14. CortesPRAlbarracín OrioAGRegueiraMPiñasGEEcheniqueJ 2008 Characterization of in vitro-generated and clinical optochin-resistant strains of Streptococcus pneumoniae isolated from Argentina. J Clin Microbiol 46 1930 1934

15. Di GuilmiAMMouzNAndrieuJPHoskinsJJaskunasSR 1998 Identification, purification, and characterization of transpeptidase and glycosyltransferase domains of Streptococcus pneumoniae penicillin-binding protein 1a. J Bacteriol 180 5652 5659

16. MorlotCZapunADidebergOVernetT 2003 Growth and division of Streptococcus pneumoniae: localization of the high molecular weight penicillin-binding proteins during the cell cycle. Mol Microbiol 50 845 855

17. DanielRAErringtonJ 2003 Control of cell morphogenesis in bacteria: two distinct ways to make a rod-shaped cell. Cell 113 767 776

18. DesaiBVMorrisonDA 2006 An unstable competence-induced protein, CoiA, promotes processing of donor DNA after uptake during genetic transformation in Streptococcus pneumoniae. J Bacteriol 188 5177 5186

19. LanGWolgemuthCWSunSX 2007 Z-ring force and cell shape during division in rod-like bacteria. Proc Natl Acad Sci U S A 104 16110 16115

20. LutkenhausJAddinallSG 1997 Bacterial cell division and the Z ring. Annu Rev Biochem 66 93 116

21. AnderssonDILevinBR 1999 The biological cost of antibiotic resistance. Curr Opin Microbiol 2 489 493

22. BjorkmanJAnderssonDI 2000 The cost of antibiotic resistance from a bacterial perspective. Drug Resist Updat 3 237 245

23. DowsonCGHutchisonABranniganJAGeorgeRCHansmanD 1989 Horizontal transfer of penicillin-binding protein genes in penicillin-resistant clinical isolates of Streptococcus pneumoniae. Proc Natl Acad Sci U S A 86 8842 8846

24. ReynoldsMG 2000 Compensatory Evolution in Rifampin-Resistant Escherichia coli. Genetics 156 1471 1481

25. GagneuxSLongCDSmallPMVanTSchoolnikGK 2006 The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312 1944 1946

26. BjorkholmBSjolundMFalkPGBergOGEngstrandL 2001 Mutation frequency and biological cost of antibiotic resistance in Helicobacter pylori. Proc Natl Acad Sci U S A 98 14607 14612

27. BottgerECSpringerBPletschetteMSanderP 1998 Fitness of antibiotic-resistant microorganisms and compensatory mutations. Nat Med 4 1343 1344

28. MarcussonLLFrimodt-MollerNHughesD 2009 Interplay in the selection of fluoroquinolone resistance and bacterial fitness. PLoS Pathog 5 e1000541

29. ZapunAVernetTPinhoMG 2008 The different shapes of cocci. FEMS Microbiol Rev 32 345 360

30. MorlotCNoirclerc-SavoyeMZapunADidebergOVernetT 2004 The D,D-carboxypeptidase PBP3 organizes the division process of Streptococcus pneumoniae. Mol Microbiol 51 1641 1648

31. PophamDLYoungKD 2003 Role of penicillin-binding proteins in bacterial cell morphogenesis. Curr Opin Microbiol 6 594 599

32. VarmaAYoungKD 2004 FtsZ collaborates with penicillin binding proteins to generate bacterial cell shape in Escherichia coli. J Bacteriol 186 6768 6774

33. VinellaDJoseleau-PetitDThevenetDBoulocPD'AriR 1993 Penicillin-binding protein 2 inactivation in Escherichia coli results in cell division inhibition, which is relieved by FtsZ overexpression. J Bacteriol 175 6704 6710

34. PernotLChesnelLLe GouellecACroizeJVernetT 2004 A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics. J Biol Chem 279 16463 16470

35. LuWPKincaidESunYBauerMD 2001 Kinetics of beta-lactam interactions with penicillin-susceptible and -resistant penicillin-binding protein 2x proteins from Streptococcus pneumoniae. Involvement of acylation and deacylation in beta-lactam resistance. J Biol Chem 276 31494 31501

36. LefevreJCBertrandMAFauconG 1995 Molecular analysis by pulsed-field gel electrophoresis of penicillin-resistant Streptococcus pneumoniae from Toulouse, France. Eur J Clin Microbiol Infect Dis 14 491 497

37. CLSI CaLSI 2007 Performance Standards for Antimicrobial Susceptibility Testing; Seventeenth edition Information Supplement. CLSI document M100-S17 [ISBN1-56238-625-5]. Wayne, Pennsylvania Clinical and Laboratory Standards Institute

38. PinasGECortesPROrioAGEcheniqueJ 2008 Acidic stress induces autolysis by a CSP-independent ComE pathway in Streptococcus pneumoniae. Microbiology 154 1300 1308

39. LenskiRE 1991 Quantifying fitness and gene stability in microorganisms. Biotechnology 15 173 192

40. BjorkmanJNagaevIBergOGHughesDAnderssonDI 2000 Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistance. Science 287 1479 1482

41. LaraBRicoAIPetruzzelliSSantonaADumasJ 2005 Cell division in cocci: localization and properties of the Streptococcus pneumoniae FtsA protein. Mol Microbiol 55 699 711

42. HansenMCPalmerRJJrUdsenCWhiteDCMolinS 2001 Assessment of GFP fluorescence in cells of Streptococcus gordonii under conditions of low pH and low oxygen concentration. Microbiology 147 1383 1391

43. ClaverysJPDintilhacAPestovaEVMartinBMorrisonDA 1995 Construction and evaluation of new drug-resistance cassettes for gene disruption mutagenesis in Streptococcus pneumoniae, using an ami test platform. Gene 164 123 128

44. Trieu-CuotPCarlierCPoyart-SalmeronCCourvalinP 1991 Shuttle vectors containing a multiple cloning site and a lacZ alpha gene for conjugal transfer of DNA from Escherichia coli to gram-positive bacteria. Gene 102 99 104

45. NobleJEBaileyMJ 2009 Quantitation of protein. Methods Enzymol 463 73 95