title: Role of the Stringent Stress Response in the Antibiotic Resistance Phenotype of Methicillin-Resistant Staphylococcus aureus.
abstract: Resistance to beta-lactam antibiotics in methicillin-resistantStaphylococcus aureus(MRSA) requires the presence of an acquired genetic determinant,mecAormecC, which encode penicillin-binding protein PBP2A or PBP2A', respectively. Although all MRSA strains share a mechanism of resistance, the phenotypic expression of beta-lactam resistance shows considerable strain-to-strain variation. The stringent stress response, a stress response that results from nutrient limitation, was shown to play a key role in determining the resistance level of an MRSA strain. In the present study, we validated the impact of the stringent stress response on transcription and translation ofmecAin the MRSA clinical isolate strain N315, which also carries known regulatory genes (mecI/mecR1/mecR2andblaI/blaR1) formecAtranscription. We showed that the impact of the stringent stress response on the resistance level may be restricted to beta-lactam resistance based on a "foreign" determinant such asmecA, as opposed to resistance based on mutations in the nativeS. aureusdeterminantpbpB(encoding PBP2). Our observations demonstrate that high-level resistance mediated by the stringent stress response follows the current model of beta-lactam resistance in which the native PBP2 protein is also essential for expression of the resistance phenotype. We also show that theStaphylococcus sciuri pbpDgene (also calledmecAI), the putative evolutionary precursor ofmecA, confers oxacillin resistance in anS. aureusstrain, generating a heterogeneous phenotype that can be converted to high and homogenous resistance by induction of the stringent stress response in the bacteria.
authors.affiliation: Laboratory of Microbiology & Infectious Diseases, The Rockefeller University, New York, New York, USA.
authors.forename: Sandra
authors.initials: S
authors.lastname: Aedo
authors.affiliation: Laboratory of Microbiology & Infectious Diseases, The Rockefeller University, New York, New York, USA tomasz@rockefeller.edu.
authors.forename: Alexander
authors.initials: A
authors.lastname: Tomasz
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000235:genetics* / Q000378:metabolism; D015964:Gene Expression Regulation, Bacterial; D005809:Genes, Regulator; D008712:Methicillin / Q000494:pharmacology; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D010068:Oxacillin / Q000494:pharmacology; D046915:Penicillin-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D010406:Penicillins / Q000494:pharmacology; D010641:Phenotype; D014176:Protein Biosynthesis; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D013045:Species Specificity; D013312:Stress, Physiological; D014158:Transcription, Genetic; D018440:beta-Lactam Resistance / Q000235:genetics*; D047090:beta-Lactams / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D010406:Penicillins; D020033:Protein Isoforms; D047090:beta-Lactams; C487789:mecA protein, Staphylococcus aureus; D008712:Methicillin; D010068:Oxacillin
references.citation: J Antimicrob Chemother. 2009 Jul;64(1):37-45
references.pmid: 19457930
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Antimicrob Agents Chemother. 2012 Feb;56(2):787-804
references.pmid: 22106209
references.citation: J Biol Chem. 2012 Oct 26;287(44):36854-63
references.pmid: 22977239
references.citation: Microb Drug Resist. 2013 Jun;19(3):153-9
references.pmid: 23659600
references.citation: PLoS One. 2013;8(8):e73512
references.pmid: 24013956
references.citation: PLoS One. 2013;8(12):e82814
references.pmid: 24349368
references.citation: MBio. 2014;5(2):e01000
references.pmid: 24713324
references.citation: J Bacteriol. 2003 Jan;185(2):645-53
references.pmid: 12511511
references.citation: Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9786-91
references.pmid: 15213324
references.citation: J Bacteriol. 1984 May;158(2):513-6
references.pmid: 6563036
references.citation: Antimicrob Agents Chemother. 1991 Jan;35(1):124-9
references.pmid: 2014967
references.citation: J Biol Chem. 1992 Jun 5;267(16):11255-9
references.pmid: 1317861
references.citation: Eur J Clin Microbiol Infect Dis. 1993;12 Suppl 1:S13-8
references.pmid: 8477757
references.citation: J Antimicrob Chemother. 1994 Jan;33(1):7-24
references.pmid: 8157576
references.citation: Antimicrob Agents Chemother. 1994 Apr;38(4):724-8
references.pmid: 8031036
references.citation: Antimicrob Agents Chemother. 1996 Dec;40(12):2680-5
references.pmid: 9124822
references.citation: Microb Drug Resist. 1996 Winter;2(4):377-91
references.pmid: 9158808
references.citation: Antimicrob Agents Chemother. 1999 Jun;43(6):1449-58
references.pmid: 10348769
references.citation: J Bacteriol. 2005 Mar;187(5):1815-24
references.pmid: 15716453
references.citation: Microbiology. 2006 Sep;152(Pt 9):2549-58
references.pmid: 16946250
references.citation: Biochemistry. 2007 Jul 10;46(27):8050-7
references.pmid: 17567045
references.citation: J Bacteriol. 2008 Jan;190(2):508-14
references.pmid: 18024515
references.citation: Curr Opin Microbiol. 2008 Apr;11(2):100-5
references.pmid: 18359660
references.citation: Annu Rev Microbiol. 2008;62:35-51
references.pmid: 18454629
references.citation: Antimicrob Agents Chemother. 2008 Nov;52(11):3955-66
references.pmid: 18725435
references.citation: PLoS One. 2014;9(6):e99605
references.pmid: 24932751
references.citation: Annu Rev Biochem. 2015;84:577-601
references.pmid: 26034890
references.citation: J Bacteriol. 2001 Apr;183(8):2417-24
references.pmid: 11274099
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 11;98(19):10886-91
references.pmid: 11517340
references.citation: J Bacteriol. 2001 Nov;183(22):6525-31
references.pmid: 11673420
references.citation: J Bacteriol. 2001 Dec;183(23):6862-8
references.pmid: 11698375
references.citation: Lancet Infect Dis. 2011 Aug;11(8):595-603
references.pmid: 21641281