Staphylococcus aureus as an infectious agent: overview of biochemistry and molecular genetics of its pathogenicity

• Autorzy: Plata K. , Rosato A.E. , Wegrzyn G.
• Języki publikacji: EN

Abstrakty

EN

 Although it is estimated that 20-30% of the general human population are carriers of Staphylococcus aureus, this bacterium is one of the most important etiological agents responsible for healthcare-associated infections. The appearance of methicillin resistant S. aureus (MRSA) strains has created serious therapeutical problems. Detailed understanding of the mechanisms of S. aureus infections seems necessary to develop new effective therapies against this pathogen. In this article, we present an overview of the biochemical and genetic mechanisms of pathogenicity of S. aureus strains. Virulence factors, organization of the genome and regulation of expression of genes involved in virulence, and mechanisms leading to methicilin resistance are presented and briefly discussed.

Słowa kluczowe

EN

bacteria; biosynthesis; methicillin resistance; infection; toxin; pathogenicity gene; virulence factor; plasmid; cell wall structure; gene regulation; virulence; Staphylococcus aureus; molecular genetics; biochemistry

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2009
• Tom: 56
• Numer: 4
• Opis fizyczny: p.597-612,fig.,ref.

Twórcy

autor

Plata K.

• University of Gdansk, Kladki 24, 80-822 Gdansk, Poland

autor

Rosato A.E.

autor

Wegrzyn G.

Bibliografia

• Arciola CR, Baldassarri L, Montanaro L (2001a) Presence of icaA and icaD genes and slime production in a collection of staphylococcal strains from catheter-associated infections. J Clin Microbiol 39: 2151-2156. 
• Arciola CR, Campoccia D, Borrelli AM, Donati ME, Montanaro L (2001b) Congo red agar plate method: improved accuracy and new extended application to Staphylococcus aureus. New Microbiol 24: 355-363. 
• Baba T, Takeuchi F, Kuroda M, Yuzawa H, Aoki K, Oguchi A et al. (2002) Genome and virulence determinants of high virulence community-acquired MRSA. Lancet 359: 1819-1827. 
• Baba T, Takeuchi F, Kuroda M, Ito T, Yuzawa H, Hiramatsu K (2004) The Staphylococcus aureus genome. Harwood Publishing Limited, West Sussex, England.
• Baker MD, Acharya KR (2004) Superantigens: structure-function relationships. Int J Med Microbiol 293: 529-537. 
• Barrett D, Leimkuhler C, Chen L, Walker D, Kahne D, Walker S (2005) Kinetic characterization of the glycosyltransferase module of Staphylococcus aureus PBP2. J Bacteriol 187: 2215-2217. 
• Bates DM, von Eiff C, McNamara PJ, Peters G, Yeaman MR, Bayer AS, Proctor RA (2003) Staphylococcus aureus menD and hemB mutants are as infective as the parent strains but the menadione biosynthetic mutant persists within the kidney. J Infect Dis 187: 1654-1661. 
• Berger-Bachi B (1994) Expression of resistance to methicillin. Trends Microbiol 2: 389-393. 
• Berger-Bachi B (1999) Genetic basis of methicillin resistance in Staphylococcus aureus. Cell Mol Life Sci 56: 764-770. 
• Berger-Bachi B, Rohrer S (2002) Factors influencing methicillin resistance in staphylococci. Arch Microbiol 178: 165-171. 
• Berger-Bachi B, Strassle A, Gustafson JE, Kayser FH (1992) Mapping and characterization of multiple chromosomal factors involved in methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 36: 1367-1373. 
• Berger-Bachi B, Tschierske M (1998) Role of fem factors in methicillin resistance. Drug Resist Updat 1: 325-335. 
• Boisset S, Geissmann T, Huntzinger E, Fechter P, Bendridi N, Possedko M et al. (2007) Staphylococcus aureus RNAIII coordinately represses the synthesis of virulence factors and the transcription regulator Rot by an antisense mechanism. Genes Dev 21: 1353-1366. 
• Bouhss A, Trunkfield AE, Bugg TD, Mengin-Lecreulx D (2008) The biosynthesis of peptidoglycan lipid-linked intermediates. FEMS Microbiol Rev 32: 208-233. 
• Chambers HF (1997) Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implications. Clin Microbiol Rev 10: 781-791. 
• Chambers HF (2003) Solving staphylococcal resistance to beta-lactams. Trends Microbiol 11: 145-148. 
• Chambers HF (2004) Antimicrobial resistance and therapy. In Staphylococcus aureus Molecular and Clinical Aspects. Harwood Publisher Limited, West Sussex, England.
• Chatterjee AN (1969) Use of bacteriophage-resistant mutants to study the nature of the bacteriophage receptor site of Staphylococcus aureus. J Bacteriol 98: 519-527. 
• Clements MO, Watson SP, Poole RK, Foster SJ (1999) CtaA of Staphylococcus aureus is required for starvation survival recovery cytochrome biosynthesis. J Bacteriol 181: 501-507. 
• Crossley KB, Archer GL (1997) The Staphylococci in human disease. Churchill Livingstone.
• de Jonge BL, Tomasz A (1993) Abnormal peptidoglycan produced in a methicillin-resistant strain of Staphylococcus aureus grown in the presence of methicillin: functional role for penicillin-binding protein 2A in cell wall synthesis. Antimicrob Agents Chemother 37: 342-346. 
• Deurenberg RH, Stobberingh EE (2008) The evolution of Staphylococcus aureus. Infect Genet Evol 8: 747-763. 
• Deurenberg RH, Stobberingh EE (2009) The molecular evolution of hospital- and community-associated methicillin-resistant Staphylococcus aureus. Curr Mol Med 9: 100-115. 
• Deurenberg RH, Vink C, Kalenic S, Friedrich AW, Bruggeman CA, Stobberingh EE (2007) The molecular evolution of methicillin-resistant Staphylococcus aureus. Clin Microbiol Infect 13: 222-235. 
• Diekema DJ, Pfaller MA, Schmitz FJ, Smayevsky J, Bell J, Jones RN, Beach M (2001) Survey of infections due to Staphylococcus species: frequency of occurrence and antimicrobial susceptibility of isolates collected in the United States, Canada, Latin America, Europe, the Western Pacific region for the SENTRY Antimicrobial Surveillance Program 1997-1999. Clin Infect Dis 32 (Suppl 2): S114-S132. 
• Diep BA, Gill SR, Chang RF, Phan TH, Chen JH, Davidson MG et al. (2006) Complete genome sequence of USA300 an epidemic clone of community-acquired meticillin-resistant Staphylococcus aureus. Lancet 367: 731-739. 
• Diep BA, Stone GG, Basuino L, Graber CJ, Miller A, des Etages SA et al. (2008) The arginine catabolic mobile element and staphylococcal chromosomal cassette mec linkage: convergence of virulence and resistance in the USA300 clone of methicillin-resistant Staphylococcus aureus. J Infect Dis 197: 1523-1530. 
• Dzwonkowska J, Kurlenda J, Baczkowski B, Mazurkiewicz S, Uzunov I, Ziolkowski W, Markowicz A (2007) The effect of antibiotic therapy on the incidence of Staphylococcus aureus infections in orthopaedic patients. Ortop Traumatol Rehabil 9: 532-547. 
• Ender M, McCallum N, Berger-Bächi B (2008) Impact of mecA promoter mutations on mecA expression and beta-lactam resistance levels. Int J Med Microbiol 298: 607-617. 
• Fey PD, Said-Salim B, Rupp ME, Hinrichs SH, Boxrud DJ, Davis CC et al. (2003) Comparative molecular analysis of community- or hospital-acquired methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 47: 196-203. 
• Finan JE, Rosato AE, Dickinson TM, Ko D, Archer GL (2002) Conversion of oxacillin-resistant staphylococci from heterotypic to homotypic resistance expression. Antimicrob Agents Chemother 46: 24-30. 
• Fitzpatrick F, Humphreys H, O'Gara JP (2005) The genetics of staphylococcal biofilm formation - will a greater understanding of pathogenesis lead to better management of device-related infection? Clin Microbiol Infect 11: 967-973. 
• Foster TJ (2005) Immune evasion by staphylococci. Nat Rev Microbiol 3: 948-958. 
• Foster TJ, Hook M (1998) Surface protein adhesins of Staphylococcus aureus. Trends Microbiol 6: 484-488. 
• Frere JM (1995) Beta-lactamases and bacterial resistance to antibiotics. Mol Microbiol 16: 385-395. 
• Gaisford WC, Reynolds PE (1989) Methicillin resistance in Staphylococcus epidermidis. Relationship between the additional penicillin-binding protein and an attachment transpeptidase. Eur J Biochem 185: 211-218. 
• Gally D, Archibald AR (1993) Cell wall assembly in Staphylococcus aureus: proposed absence of secondary crosslinking reactions. J Gen Microbiol 139: 1907-1913. 
• Gill SR, Fouts DE, Archer GL, Mongodin EF, Deboy RT, Ravel J et al. (2005) Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain. J Bacteriol 187: 2426-2438. 
• Goffin C, Ghuysen JM (1998) Multimodular penicillin-binding proteins: an enigmatic family of orthologs and paralogs. Microbiol Mol Biol Rev 62: 1079-1093. 
• Gordon RJ, Lowy FD (2008) Pathogenesis of methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis 46 (Suppl 5): S350-S359. 
• Gregory PD, Lewis RA, Curnock SP, Dyke KG (1997) Studies of the repressor (BlaI) of beta-lactamase synthesis in Staphylococcus aureus. Mol Microbiol 24: 1025-1037. 
• Grinholc M, Wegrzyn G, Kurlenda J (2007) Evaluation of biofilm production and prevalence of the icaD gene in methicillin-resistant and methicillin-susceptible Staphylococcus aureus strains isolated from patients with nosocomial infections and carriers. FEMS Immunol Med Microbiol 50: 375-379. 
• Grinholc M, Kawiak A, Kurlenda J, Graczyk A, Bielawski KP (2008) Photodynamic effect of protoporphyrin diarginate (PPArg2) on methicillin-resistant Staphylococcus aureus and human dermal fibroblasts. Acta Biochim Polon 55: 85-90. 
• Hackbarth CJ, Miick C, Chambers HF (1994) Altered production of penicillin-binding protein 2a can affect phenotypic expression of methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 38: 2568-2571. 
• Hanssen AM, Ericson Sollid JU (2006) SCCmec in staphylococci: genes on the move. FEMS Immunol Med Microbiol 46: 8-20. 
• Hartleib J, Kohler N, Dickinson RB, Chhatwal GS, Sixma JJ, Hartford OM et al. (2000) Protein A is the von Willebrand factor binding protein on Staphylococcus aureus. Blood 96: 2149-2156. 
• Hauck CR, Ohlsen K (2006) Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus. Curr Opin Microbiol 9: 5-11. 
• Heyman D (2004) Control of Communicable Diseases Manual. 18th edn. American Public Health Association, Washington DC.
• Hiramatsu K, Cui L, Kuroda M, Ito T (2001) The emergence and evolution of methicillin-resistant Staphylococcus aureus. Trends Microbiol 9: 486-493. 
• Holden MT, Feil EJ, Lindsay JA, Peacock SJ, Day NP, Enright MC et al. (2004) Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance. Proc Natl Acad Sci USA 101: 9786-9791. 
• Ito T, Katayama Y, Hiramatsu K (1999) Cloning and nucleotide sequence determination of the entire mec DNA of pre-methicillin-resistant Staphylococcus aureus N315. Antimicrob Agents Chemother 43: 1449-1458. 
• Ito T, Katayama Y, Asada K, Mori N, Tsutsumimoto K, Tiensasitorn C, Hiramatsu K (2001) Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 45: 1323-1336. 
• Ito T, Ma XX, Takeuchi F, Okuma K, Yuzawa H, Hiramatsu K (2004) Novel type V staphylococcal cassette chromosome mec driven by a novel cassette chromosome recombinase ccrC. Antimicrob Agents Chemother 48: 2637-2651. 
• Janzon L, Arvidson S (1990) The role of the delta-lysin gene (hld) in the regulation of virulence genes by the accessory gene regulator (agr) in Staphylococcus aureus. EMBO J 9: 1391-1399. 
• Jurczak A, Szramka B, Grinholc M, Legendziewicz J, Bielawski KP (2008) Photodynamic effect of lanthanide derivatives of meso-tetra(N-methyl-4-pyridyl)porphine against Staphylococcus aureus. Acta Biochim Polon 55: 581-585. 
• Kaneko J, Kamio Y (2004) Bacterial two-component and hetero-heptameric pore-forming cytolytic toxins: structures pore-forming mechanism organization of the genes. Biosci Biotechnol Biochem 68: 981-1003. 
• Katayama Y, Ito T, Hiramatsu K (2000) A new class of genetic element staphylococcus cassette chromosome mec encodes methicillin resistance in Staphylococcus aureus. Antimicrob Agents Chemother 44: 1549-1555. 
• Katayama Y, Ito T, Hiramatsu K (2001) Genetic organization of the chromosome region surrounding mecA in clinical staphylococcal strains: role of IS431-mediated mecI deletion in expression of resistance in mecA-carrying low-level methicillin-resistant Staphylococcus haemolyticus. Antimicrob Agents Chemother 45: 1955-1963. 
• Katayama Y, Robinson DA, Enright MC, Chambers HF (2005) Genetic background affects stability of mecA in Staphylococcus aureus. J Clin Microbiol 43: 2380-2383. 
• Kluytmans J, van BA, Verbrugh H (1997) Nasal carriage of Staphylococcus aureus: epidemiology underlying mechanisms associated risks. Clin Microbiol Rev 10: 505-520. 
• Kobayashi N, Urasawa S, Uehara N, Watanabe N (1999) Distribution of insertion sequence-like element IS1272 and its position relative to methicillin resistance genes in clinically important Staphylococci. Antimicrob Agents Chemother 43: 2780-2782. 
• Komatsuzawa H, Suzuki J, Sugai M, Miyake Y, Suginaka H (1994) The effect of Triton X-100 on the in-vitro susceptibility of methicillin-resistant Staphylococcus aureus to oxacillin. J Antimicrob Chemother 34: 885-897. 
• Kotzin BL, Leung DY, Kappler J, Marrack P (1993) Superantigens and their potential role in human disease. Adv Immunol 54: 99-166. 
• Kurlenda J, Grinholc M, Jasek K, Wegrzyn G (2007) RAPD typing of methicillin-resistant Staphylococcus aureus: a 7-year experience in a Polish hospital. Med Sci Monit 13: MT13-MT18. 
• Kurlenda J, Grinholc M, Krzyszton-Russjan J, Wisniewska K (2009) Epidemiological investigation of nosocomial outbreak of staphylococcal skin diseases in neonatal ward. Antonie Van Leeuwenhoek 95: 387-394. 
• Kuroda M, Ohta T, Uchiyama I, Baba T, Yuzawa H, Kobayashi I et al. (2001) Whole genome sequencing of meticillin-resistant Staphylococcus aureus. Lancet 357: 1225-1240. 
• Kwan T, Liu J, DuBow M, Gros P, Pelletier J (2005) The complete genomes and proteomes of 27 Staphylococcus aureus bacteriophages. Proc Natl Acad Sci USA 102: 5174-5179. 
• Labischinski H (1992) Consequences of the interaction of beta-lactam antibiotics with penicillin binding proteins from sensitive and resistant Staphylococcus aureus strains. Med Microbiol Immunol 181: 241-265. 
• Lannergard J, von EC, Sander G, Cordes T, Seggewiss J, Peters G et al. (2008) Identification of the genetic basis for clinical menadione-auxotrophic small-colony variant isolates of Staphylococcus aureus. Antimicrob Agents Chemother 52: 4017-4022. 
• Lim D, Strynadka NC (2002) Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol 9: 870-876. 
• Lindsay JA, Holden MT (2004) Staphylococcus aureus: superbug, super genome? Trends Microbiol 12: 378-385. 
• Lindsay JA, Ruzin A, Ross HF, Kurepina N, Novick RP (1998) The gene for toxic shock toxin is carried by a family of mobile pathogenicity islands in Staphylococcus aureus. Mol Microbiol 29: 527-543. 
• Liu GY, Essex A, Buchanan JT, Datta V, Hoffman HM, Bastian JF et al. (2005) Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity. J Exp Med 202: 209-215. 
• Mallorqui-Fernandez G, Marrero A, Garcia-Pique S, Garcia-Castellanos R, Gomis-Ruth FX (2004) Staphylococcal methicillin resistance: fine focus on folds and functions. FEMS Microbiol Lett 235: 1-8. 
• Mann NH (2008) The potential of phages to prevent MRSA infections. Res Microbiol 159: 400-405. 
• Menestrina G, Serra MD, Prevost G (2001) Mode of action of beta-barrel pore-forming toxins of the staphylococcal alpha-hemolysin family. Toxicon 39: 1661-1672. 
• Milheirico C, Oliveira DC, de LH (2007) Update to the multiplex PCR strategy for assignment of mec element types in Staphylococcus aureus. Antimicrob Agents Chemother 51: 3374-3377. 
• Morfeldt E, Taylor D, von Gabain A, Arvidson S (1995) Activation of alpha-toxin translation in Staphylococcus aureus by the trans-encoded antisense RNA, RNAIII. EMBO J 14: 4569-4577. 
• Murakami K, Tomasz A (1989) Involvement of multiple genetic determinants in high-level methicillin resistance in Staphylococcus aureus. J Bacteriol 171: 874-879. 
• Niemeyer DM, Pucci MJ, Thanassi JA, Sharma VK, Archer GL (1996) Role of mecA transcriptional regulation in the phenotypic expression of methicillin resistance in Staphylococcus aureus. J Bacteriol 178: 5464-5471. 
• Noto MJ, Kreiswirth BN, Monk AB, Archer GL (2008) Gene acquisition at the insertion site for SCCmec the genomic island conferring methicillin resistance in Staphylococcus aureus. J Bacteriol 190: 1276-1283. 
• Novick RP (1989) Staphylococcal plasmids and their replication. Annu Rev Microbiol 43: 537-565. 
• Novick RP (2003a) Autoinduction and signal transduction in the regulation of staphylococcal virulence. Mol Microbiol 48: 1429-1449. 
• Novick RP (2003b) Mobile genetic elements and bacterial toxinoses: the superantigen-encoding pathogenicity islands of Staphylococcus aureus. Plasmid 49: 93-105. 
• Novick RP, Geisinger E (2008) Quorum sensing in staphylococci. Annu Rev Genet 42: 541-564. 
• Okuma K, Iwakawa K, Turnidge JD, Grubb WB, Bell JM, O'Brien FG et al. (2002) Dissemination of new methicillin-resistant Staphylococcus aureus clones in the community. J Clin Microbiol 40: 4289-4294. 
• Oliveira DC, Tomasz A, de Lencastre H (2001) The evolution of pandemic clones of methicillin-resistant Staphylococcus aureus: identification of two ancestral genetic backgrounds and the associated mec elements. Microb Drug Resist 7: 349-361. 
• Patti JM, Bremell T, Krajewska-Pietrasik D, Abdelnour A, Tarkowski A, Ryden C, Hook M (1994) The Staphylococcus aureus collagen adhesin is a virulence determinant in experimental septic arthritis. Infect Immun 62: 152-161. 
• Pinho MG, Filipe SR, de Lencastre H, Tomasz A (2001) Complementation of the essential peptidoglycan transpeptidase function of penicillin-binding protein 2 (PBP2) by the drug resistance protein PBP2A in Staphylococcus aureus. J Bacteriol 183: 6525-6531. 
• Potempa J, Fedak D, Dubin A, Mast A, Travis J (1991) Proteolytic inactivation of alpha-1-anti-chymotrypsin. Sites of cleavage and generation of chemotactic activity. J Biol Chem 266: 21482-21487. 
• Proctor RA, van Langevelde P, Kristjansson M, Maslow JN, Arbeit RD (1995) Persistent and relapsing infections associated with small-colony variants of Staphylococcus aureus. Clin Infect Dis 20: 95-102. 
• Proctor RA, von Eiff C, Kahl BC, Becker K, McNamara P, Herrmann M, Peters G (2006) Small colony variants: a pathogenic form of bacteria that facilitates persistent and recurrent infections. Nat Rev Microbiol 4: 295-305. 
• Rice LB (2006) Antimicrobial resistance in gram-positive bacteria. Am J Med 119: S11-S19. 
• Robinson DA, Enright MC (2003) Evolutionary models of the emergence of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 47: 3926-3934. 
• Rohde H, Knobloch JK, Horstkotte MA, Mack D (2001) Correlation of Staphylococcus aureus icaADBC genotype and biofilm expression phenotype. J Clin Microbiol 39: 4595-4596. 
• Rohrer S, Maki H, Berger-Bachi B (2003) What makes resistance to methicillin heterogeneous? J Med Microbiol 52: 605-607. 
• Rosato AE, Craig WA, Archer GL (2003a) Quantitation of mecA transcription in oxacillin-resistant Staphylococcus aureus clinical isolates. J Bacteriol 185: 3446-3452. 
• Rosato AE, Kreiswirth BN, Craig WA, Eisner W, Climo MW, Archer GL (2003b) mecA-blaZ corepressors in clinical Staphylococcus aureus isolates. Antimicrob Agents Chemother 47: 1460-1463. 
• Ruzin A, Lindsay J, Novick RP (2001) Molecular genetics of SaPI1 - a mobile pathogenicity island in Staphylococcus aureus. Mol Microbiol 41: 365-377. 
• Ryan KJ, Ray CG (2004) Sherris Medical Microbiology: An Introduction to Infectious Diseases. 4th edn. McGraw Hill Publishers.
• Safo MK, Ko TP, Musayev FN, Zhao Q, Wang AH, Archer GL (2006) Structure of the MecI repressor from Staphylococcus aureus in complex with the cognate DNA operator of mec. Acta Crystallogr Sect F Struct Biol Cryst Commun 62: 320-324. 
• Scheffers DJ, Pinho MG (2005) Bacterial cell wall synthesis: new insights from localization studies. Microbiol Mol Biol Rev 69: 585-607. 
• Schito GC (2006) The importance of the development of antibiotic resistance in Staphylococcus aureus. Clin Microbiol Infect 12 (Suppl 1): 3-8. 
• Switalski LM, Patti JM, Butcher W, Gristina AG, Speziale P, Hook M (1993) A collagen receptor on Staphylococcus aureus strains isolated from patients with septic arthritis mediates adhesion to cartilage. Mol Microbiol 7: 99-107. 
• Tomasz A, Nachman S, Leaf H (1991) Stable classes of phenotypic expression in methicillin-resistant clinical isolates of staphylococci. Antimicrob Agents Chemother 35: 124-129. 
• Ubeda C, Maiques E, Knecht E, Lasa I, Novick RP, Penades JR (2005) Antibiotic-induced SOS response promotes horizontal dissemination of pathogenicity island-encoded virulence factors in staphylococci. Mol Microbiol 56: 836-844. 
• Vollmer W, Blanot D, de Pedro MA (2008) Peptidoglycan structure and architecture. FEMS Microbiol Rev 32: 149-167. 
• von Eiff C (2008) Staphylococcus aureus small colony variants: a challenge to microbiologists and clinicians. Int J Antimicrob Agents 31: 507-510. 
• Wang QM, Peery RB, Johnson RB, Alborn WE, Yeh WK, Skatrud PL (2001) Identification and characterization of a monofunctional glycosyltransferase from Staphylococcus aureus. J Bacteriol 183: 4779-4785. 
• Wegrzyn G (2005) What does "plasmid biology" currently mean? Summary of the Plasmid Biology 2004 Meeting. Plasmid 53: 14-22. 
• Weller TM (1999) The distribution of mecA mecR1 and mecI and sequence analysis of mecI and the mec promoter region in staphylococci expressing resistance to methicillin. J Antimicrob Chemother 43: 15-22. 
• Wertheim HF, Melles DC, Vos MC, van Leeuwen W, van Belkum A, Verbrugh HA, Nouwen JL (2005) The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis 5: 751-762. 
• Wielders CL, Vriens MR, Brisse S, de Graaf-Miltenburg LA, Troelstra A, Fleer A et al. (2001) In-vivo transfer of mecA DNA to Staphylococcus aureus [corrected]. Lancet 357: 1674-1675. 
• Wilke MS, Lovering AL, Strynadka NC (2005) Beta-lactam antibiotic resistance: a current structural perspective. Curr Opin Microbiol 8: 525-533. 
• Williams Re, Jevons Mp, Shooter Ra, Hunter Cj, Girling Ja, Griffiths Jd, Taylor Gw (1959) Nasal staphylococci and sepsis in hospital patients. Br Med J 2: 658-662. 
• Wisplinghoff H, Rosato AE, Enright MC, Noto M, Craig W, Archer GL (2003) Related clones containing SCCmec type IV predominate among clinically significant Staphylococcus epidermidis isolates. Antimicrob Agents Chemother 47: 3574-3579. 
• Wu SW, de Lencastre H, Tomasz A (2001) Recruitment of the mecA gene homologue of Staphylococcus sciuri into a resistance determinant and expression of the resistant phenotype in Staphylococcus aureus. J Bacteriol 183: 2417-2424. 
• Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF (2001) A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science 291: 1962-1965. 
• Zhang K, McClure JA, Elsayed S, Conly JM (2009) Novel staphylococcal cassette chromosome mec type tentatively designated type VIII harboring class A mec and type 4 ccr gene complexes in a Canadian epidemic strain of methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 53: 531-540. 
• Zygmunt DJ, Stratton CW, Kernodle DS (1992) Characterization of four beta-lactamases produced by Staphylococcus aureus. Antimicrob Agents Chemother 36: 440-445.