Multidrug efflux pumps in Staphylococcus aureus and their clinical implications

Journal of Microbiology

Volumn 54, Issue 1, 2016, Pages 1-8

  Jang, Soojin ^a  

^a Institute Pasteur Korea   (South Korea)

Author keywords

MRSA; multidrug efflux pumps; multidrug resistance; Staphylococcus aureus

Indexed keywords

ABC TRANSPORTER; ANTIINFECTIVE AGENT; MULTIDRUG RESISTANCE PROTEIN;

ANIMAL; CHEMISTRY; DRUG EFFECTS; GENETICS; HUMAN; METABOLISM; METHICILLIN RESISTANT STAPHYLOCOCCUS AUREUS; MICROBIOLOGY; MULTIDRUG RESISTANCE; PATHOGENICITY; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS AUREUS;

ANIMALS; ANTI-BACTERIAL AGENTS; ATP-BINDING CASSETTE TRANSPORTERS; DRUG RESISTANCE, MULTIPLE, BACTERIAL; HUMANS; METHICILLIN-RESISTANT STAPHYLOCOCCUS AUREUS; MULTIDRUG RESISTANCE-ASSOCIATED PROTEINS; STAPHYLOCOCCAL INFECTIONS; STAPHYLOCOCCUS AUREUS;

EID: 84953333087     PISSN: 12258873     EISSN: 19763794     Source Type: Journal    
DOI: 10.1007/s12275-016-5159-z     Document Type: Review

References (102)

1. Allignet, J. and El Solh, N. 1997. Characterization of a new staphylococcal gene, vgaB, encoding a putative ABC transporter conferring resistance to streptogramin A and related compounds. Gene202, 133–138.
2. Allignet, J., Loncle, V., and el Sohl, N. 1992. Sequence of a staphylococcal plasmid gene, vga, encoding a putative ATP-binding protein involved in resistance to virginiamycin A-like antibiotics. Gene117, 45–51.
3. Alnaseri, H., Arsic, B., Schneider, J.E., Kaiser, J.C., Scinocca, Z.C., Heinrichs, D.E., and McGavin, M.J. 2015. Inducible expression of a resistance-nodulation-division-type efflux pump in Staphylococcus aureus provides resistance to linoleic and arachidonic acids. J. Bacteriol.197, 1893–1905.
4. Baugh, S., Phillips, C.R., Ekanayaka, A.S., Piddock, L.J., and Webber, M.A. 2014. Inhibition of multidrug efflux as a strategy to prevent biofilm formation. J. Antimicrob. Chemother.69, 673–681.
5. Bayer, A.S., Kupferwasser, L.I., Brown, M.H., Skurray, R.A., Grkovic, S., Jones, T., Mukhopadhay, K., and Yeaman, M.R. 2006. Lowlevel resistance of Staphylococcus aureus to thrombin-induced platelet microbicidal protein 1 in vitro associated with qacA gene carriage is independent of multidrug efflux pump activity. Antimicrob. Agents Chemother.50, 2448–2454.
6. Bjorland, J., Steinum, T., Sunde, M., Waage, S., and Heir, E. 2003. Novel plasmid-borne gene qacJ mediates resistance to quaternary ammonium compounds in equine Staphylococcus aureus, Staphylococcus simulans, and Staphylococcus intermedius. Antimicrob. Agents Chemother.47, 3046–3052.
7. Blair, J.M., Webber, M.A., Baylay, A.J., Ogbolu, D.O., and Piddock, L.J. 2014. Molecular mechanisms of antibiotic resistance. Nat. Rev. Microbiol.13, 42–51.
8. Brown, M.H. and Skurray, R.A. 2001. Staphylococcal multidrug efflux protein QacA. J. Mol. Microbiol. Biotechnol.3, 163–170.
9. Butler, M.S., Blaskovich, M.A., and Cooper, M.A. 2013. Antibiotics in the clinical pipeline i. 2013. J. Antibiot.66, 571–591.
10. Canton, R. and Ruiz-Garbajosa, P. 2011. Co-resistance: An opportunity for the bacteria and resistance genes. Curr. Opin. Pharmacol.11, 477–485.
11. Costa, S.S., Falcao, C., Viveiros, M., Machado, D., Martins, M., Melo- Cristino, J., Amaral, L., and Couto, I. 2011. Exploring the contribution of efflux on the resistance to fluoroquinolones in clinical isolates of Staphylococcus aureus. BMC Microbiol.11, 241.
12. Costa, S.S., Mourato, C., Viveiros, M., Melo-Cristino, J., Amaral, L., and Couto, I. 2013a. Description of plasmid pSM52, harbouring the gene for the SMR efflux pump, and its involvement in resistance to biocides in a meticillin-resistant Staphylococcus aureus strain. Int. J. Antimicrob. Agents41, 490–492.
13. Costa, S.S., Viveiros, M., Amaral, L., and Couto, I. 2013b. Multidrug efflux pumps in Staphylococcus aureus: An update. Open Microbiol. J.7, 59–71.
14. Dawson, R.J. and Locher, K.P. 2006. Structure of a bacterial multidrug ABC transporter. Nature443, 180–185.
15. Dawson, R.J. and Locher, K.P. 2007. Structure of the multidrug ABC transporter Sav1866 from Staphylococcus aureus in complex with AMP-PNP. FEBS Lett.581, 935–938.
16. DeMarco, C.E., Cushing, L.A., Frempong-Manso, E., Seo, S.M., Jaravaza, T.A., and Kaatz, G.W. 2007. Efflux-related resistance to norfloxacin, dyes, and biocides in bloodstream isolates of Staphylococcus aureus. Antimicrob. Agents Chemother.51, 3235–3239.
17. Ding, Y., Fu, Y., Lee, J.C., and Hooper, D.C. 2012. Staphylococcus aureus NorD, a putative efflux pump coregulated with the Opp1 oligopeptide permease, contributes selectively to fitness in vivo. J. Bacteriol.194, 6586–6593.
18. Ding, Y., Onodera, Y., Lee, J.C., and Hooper, D.C. 2008. NorD, an efflux pump in Staphylococcus aureus strain MW2, contributes to bacterial fitness in abscesses. J. Bacteriol.190, 7123–7129.
19. Fange, D., Nilsson, K., Tenson, T., and Ehrenberg, M. 2009. Drug efflux pump deficiency and drug target resistance masking in growing bacteria. Proc. Natl. Acad. Sci. USA106, 8215–8220.
20. Farrell, D.J., Castanheira, M., Mendes, R.E., Sader, H.S., and Jones, R.N. 2012. In vitro activity of ceftaroline against multidrug-resistant Staphylococcus aureus and Streptococcus pneumoniae: A review of published studies and the aware surveillance program (2008-2010). Clin. Infect. Dis. 55 Suppl 3, S206–S214.
21. Floyd, J.L., Smith, K.P., Kumar, S.H., Floyd, J.T., and Varela, M.F. 2010. LmrS is a multidrug efflux pump of the major facilitator superfamily from Staphylococcus aureus. Antimicrob. Agents Chemother.54, 5406–5412.
22. Frempong-Manso, E., Raygada, J.L., De Marco, C.E., Seo, S.M., and Kaatz, G.W. 2009. Inability of a reserpine-based screen to identify strains overexpressing efflux pump genes in clinical isolates of Staphylococcus aureus. Int. J. Antimicrob. Agents33, 360–363.
23. Grkovic, S., Brown, M.H., Roberts, N.J., Paulsen, I.T., and Skurray, R.A. 1998. QacR is a repressor protein that regulates expression of the Staphylococcus aureus multidrug efflux pump QacA. J. Biol. Chem.273, 18665–18673.
24. Handzlik, J., Matys, A., and Kiec-Kononowicz, K. 2013. Recent advances in multi-drug resistance (MDR) efflux pump inhibitors of Gram-positive bacteria S. aureus. Antibiotics2, 17.
25. Hanses, F., Roux, C., Dunman, P.M., Salzberger, B., and Lee, J.C. 2014. Staphylococcus aureus gene expression in a rat model of infective endocarditis. Genome Med.6, 93.
26. He, G.X., Landry, M., Chen, H., Thorpe, C., Walsh, D., Varela, M.F., and Pan, H. 2014. Detection of benzalkonium chloride resistance in community environmental isolates of staphylococci. J. Med. Microbiol.63, 735–741.
27. Heir, E., Sundheim, G., and Holck, A.L. 1998. The Staphylococcus qacH gene product: A new member of the SMR family encoding multidrug resistance. FEMS Microbiol. Lett.163, 49–56.
28. Heir, E., Sundheim, G., and Holck, A.L. 1999. The qacG gene on plasmid pST94 confers resistance to quaternary ammonium compounds in staphylococci isolated from the food industry. J. Appl. Microbiol.86, 378–388.
29. Hiramatsu, K., Katayama, Y., Matsuo, M., Sasaki, T., Morimoto, Y., Sekiguchi, A., and Baba, T. 2014. Multi-drug-resistant Staphylococcus aureus and future chemotherapy. J. Infect. Chemother.20, 593–601.
30. Holmes, N.E. and Howden, B.P. 2014. What’s new in the treatment of serious MRSA infection? Curr. Opin. Infect. Dis.27, 471–478.
31. Huang, J., O’ Toole, P.W., Shen, W., Amrine-Madsen, H., Jiang, X., Lobo, N., Palmer, L.M., Voelker, L., Fan, F., Gwynn, M.N., and McDevitt, D. 2004. Novel chromosomally encoded multidrug efflux transporter MdeA in Staphylococcus aureus. Antimicrob. Agents Chemother.48, 909–917.
32. Jacquet, E., Girard, J.M., Ramaen, O., Pamlard, O., Levaique, H., Betton, J.M., Dassa, E., and Chesneau, O. 2008. ATP hydrolysis and pristinamycin IIA inhibition of the Staphylococcus aureus Vga(A), a dual ABC protein involved in streptogramin a resistance. J. Biol. Chem.283, 25332–25339.
33. Johnson, J.G., Saye, E.J., Jimenez-Truque, N., Soper, N., Thomsen, I., Talbot, T.R., and Creech, C.B. 2013. Frequency of disinfectant resistance genes in pediatric strains of methicillin-resistant Staphylococcus aureus. Infect. Control Hosp. Epidemiol.34, 1326–1327.
34. Jones, M.E., Boenink, N.M., Verhoef, J., Kohrer, K., and Schmitz, F.J. 2000. Multiple mutations conferring ciprofloxacin resistance in Staphylococcus aureus demonstrate long-term stability in an antibiotic-free environment. J. Antimicrob. Chemother.45, 353–356.
35. Kaatz, G.W., DeMarco, C.E., and Seo, S.M. 2006. MepR, a repressor of the Staphylococcus aureus MATE family multidrug efflux pump MepA, is a substrate-responsive regulatory protein. Antimicrob. Agents Chemother.50, 1276–1281.
36. Kaatz, G.W., McAleese, F., and Seo, S.M. 2005. Multidrug resistance in Staphylococcus aureus due to overexpression of a novel multidrug and toxin extrusion (MATE) transport protein. Antimicrob. Agents Chemother.49, 1857–1864.
37. Kaatz, G.W., Moudgal, V.V., Seo, S.M., and Kristiansen, J.E. 2003. Phenothiazines and thioxanthenes inhibit multidrug efflux pump activity in Staphylococcus aureus. Antimicrob. Agents Chemother.47, 719–726.
38. Kaatz, G.W., Seo, S.M., and Ruble, C.A. 1993. Efflux-mediated fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother.37, 1086–1094.
39. Kaatz, G.W., Thyagarajan, R.V., and Seo, S.M. 2005. Effect of promoter region mutations and MgrA overexpression on transcription of norA, which encodes a Staphylococcus aureus multidrug efflux transporter. Antimicrob. Agents Chemother.49. 161–169.
40. Kalisvar Marimuthu, D.P.H. 2014. The effect of improved hand hygiene on nosocomial MRSA control. Antimicrob. Resist. Infect. Control3, 6.
41. Kosmidis, C., De Marco, C.E., Frempong-Manso, E., Seo, S.M., and Kaatz, G.W. 2010. In silico genetic correlations of multidrug efflux pump gene expression in Staphylococcus aureus. Int. J. Antimicrob. Agents36, 222–229.
42. Kosmidis, C., Schindler, B.D., Jacinto, P.L., Patel, D., Bains, K., Seo, S.M., and Kaatz, G.W. 2012. Expression of multidrug resistance efflux pump genes in clinical and environmental isolates of Staphylococcus aureus. Int. J. Antimicrob. Agents40, 204–209.
43. Kumaraswami, M., Schuman, J.T., Seo, S.M., Kaatz, G.W., and Brennan, R.G. 2009. Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA. Nucleic Acids Res.37, 1211–1224.
44. Kuroda, T. and Tsuchiya, T. 2009. Multidrug efflux transporters in the MATE family. Biochim. Biophys. Acta.1794, 763–768.
45. Kwak, Y.G., Truong-Bolduc, Q.C., Bin Kim, H., Song, K.H., Kim, E.S., and Hooper, D.C. 2013. Association of norB overexpression and fluoroquinolone resistance in clinical isolates of Staphylococcus aureus from Korea. J. Antimicrob. Chemother.68, 2766–2772.
46. Leelaporn, A., Paulsen, I.T., Tennent, J.M., Littlejohn, T.G., and Skurray, R.A. 1994. Multidrug resistance to antiseptics and disinfectants in coagulase-negative staphylococci. J. Med. Microbiol.40, 214–220.
47. Lewis, V.G., Ween, M.P., and McDevitt, C.A. 2012. The role of ATPbinding cassette transporters in bacterial pathogenicity. Protoplasma249, 919–942.
48. Li, X.Z. and Nikaido, H. 2009. Efflux-mediated drug resistance in bacteria: An update. Drugs69, 1555–1623.
49. Liu, Q., Zhao, H., Han, L., Shu, W., Wu, Q., and Ni, Y. 2015. Frequency of biocide-resistant genes and susceptibility to chlorhexidine in high-level mupirocin-resistant, methicillin-resistant Staphylococcus aureus (MuH MRSA). Diagn. Microbiol. Infect. Dis.82, 278–283.
50. Livermore, D.M. 2000. Antibiotic resistance in staphylococci. Int. J. Antimicrob. Agents 16 Suppl 1, S3–10.
51. Malachowa, N., Kobayashi, S.D., Sturdevant, D.E., Scott, D.P., and DeLeo, F.R. 2015. Insights into the Staphylococcus aureus-host interface: Global changes in host and pathogen gene expression in a rabbit skin infection model. PLoS One10, e0117713.
52. Marchi, E., Furi, L., Arioli, S., Morrissey, I., Di Lorenzo, V., Mora, D., Giovannetti, L., Oggioni, M.R., and Viti, C. 2015. Novel insight into antimicrobial resistance and sensitivity phenotypes associated to qac and norA genotypes in Staphylococcus aureus. Microbiol. Res.170, 184–194.
53. Markham, P.N. and Neyfakh, A.A. 1996. Inhibition of the multidrug transporter NorA prevents emergence of norfloxacin resistance in Staphylococcus aureus. Antimicrob. Agents Chemother.40, 2673–2674.
54. Mayer, S., Boos, M., Beyer, A., Fluit, A.C., and Schmitz, F.J. 2001. Distribution of the antiseptic resistance genes qacA, qacB and qacC in 497 methicillin-resistant and -susceptible european isolates of Staphylococcus aureus. J. Antimicrob. Chemother.47, 896–897.
55. Mitchell, B.A., Brown, M.H., and Skurray, R.A. 1998. QacA multidrug efflux pump from Staphylococcus aureus: Comparative analysis of resistance to diamidines, biguanidines, and guanylhydrazones. Antimicrob. Agents Chemother.42, 475–477.
56. Nakaminami, H., Noguchi, N., Nishijima, S., Kurokawa, I., and Sasatsu, M. 2008. Characterization of the pTZ2162 encoding multidrug efflux gene qacB from Staphylococcus aureus. Plasmid60, 108–117.
57. Narui, K., Noguchi, N., Wakasugi, K., and Sasatsu, M. 2002. Cloning and characterization of a novel chromosomal drug efflux gene in Staphylococcus aureus. Biol. Pharm. Bull.25, 1533–1536.
58. Nguyen, H.M. and Graber, C.J. 2010. Limitations of antibiotic options for invasive infections caused by methicillin-resistant Staphylococcus aureus: Is combination therapy the answer? J. Antimicrob. Chemother.65, 24–36.
59. Nikaido, H. and Takatsuka, Y. 2009. Mechanisms of RND multidrug efflux pumps. Biochim. Biophys. Acta1794, 769–781.
60. Noguchi, N., Okada, H., Narui, K., and Sasatsu, M. 2004. Comparison of the nucleotide sequence and expression of norA genes and microbial susceptibility in 21 strains of Staphylococcus aureus. Microb. Drug Resist.10, 197–203.
61. Noguchi, N., Suwa, J., Narui, K., Sasatsu, M., Ito, T., Hiramatsu, K., and Song, J.H. 2005. Susceptibilities to antiseptic agents and distribution of antiseptic-resistance genes qacA/B and SMR of methicillin-resistant Staphylococcus aureus isolated in Asia during 1998 an. 1999. J. Med. Microbiol.54, 557–565.
62. Novotna, G. and Janata, J. 2006. A new evolutionary variant of the streptogramin A resistance protein, VgaALC, from Staphylococcus haemolyticus with shifted substrate specificity towards lincosamides. Antimicrob. Agents Chemother.50, 4070–4076.
63. Oggioni, M.R., Coelho, J.R., Furi, L., Knight, D.R., Viti, C., Orefici, G., Martinez, J.L., Freitas, A.T., Coque, T.M., Morrissey, I., and consortium, B. 2015. Significant differences characterise the correlation coefficients between biocide and antibiotic susceptibility profiles in Staphylococcus aureus. Curr. Pharm. Des.21, 2054–2057.
64. Omote, H., Hiasa, M., Matsumoto, T., Otsuka, M., and Moriyama, Y. 2006. The MATE proteins as fundamental transporters of metabolic and xenobiotic organic cations. Trends Pharmacol. Sci.27, 587–593.
65. Piddock, L.J. 2006a. Clinically relevant chromosomally encoded multidrug resistance efflux pumps in bacteria. Clin. Microbiol. Rev.19, 382–402.
66. Piddock, L.J. 2006b. Multidrug-resistance efflux pumps -not just for resistance. Nat. Rev. Microbiol.4, 629–636.
67. Poole, K. 2008. Bacterial multidrug efflux pumps serve other functions. Microbe3, 179–185.
68. Qin, X., Poon, B., Kwong, J., Niles, D., Schmidt, B.Z., Rajagopal, L., and Gantt, S. 2011. Two paediatric cases of skin and soft-tissue infections due to clindamycin-resistant Staphylococcus aureus carrying a plasmid-encoded vgaA allelic variant for a putative efflux pump. Int. J. Antimicrob. Agents38, 81–83.
69. Reynolds, E., Ross, J.I., and Cove, J.H. 2003. Msr(A) and related macrolide/streptogramin resistance determinants: Incomplete transporters? Int. J. Antimicrob. Agents22, 228–236.
70. Ross, J.I., Eady, E.A., Cove, J.H., and Baumberg, S. 1995. Identification of a chromosomally encoded ABC-transport system with which the staphylococcal erythromycin exporter MsrA may interact. Gene153, 93–98.
71. Schindler, B.D., Frempong-Manso, E., DeMarco, C.E., Kosmidis, C., Matta, V., Seo, S.M., and Kaatz, G.W. 2015a. Analyses of multidrug efflux pump-like proteins encoded on the Staphylococcus aureus chromosome. Antimicrob. Agents Chemother.59, 747–748.
72. Schindler, B.D., Jacinto, P.L., Buensalido, J.A., Seo, S.M., and Kaatz, G.W. 2015b. Clonal relatedness is a predictor of spontaneous multidrug efflux pump gene overexpression in Staphylococcus aureus. Int. J. Antimicrob. Agents45, 464–470.
73. Schindler, B.D., Jacinto, P., and Kaatz, G.W. 2013. Inhibition of drug efflux pumps in Staphylococcus aureus: Current status of potentiating existing antibiotics. Future Microbiol.8, 491–507.
74. Schindler, B.D., Seo, S.M., Birukou, I., Brennan, R.G., and Kaatz, G.W. 2015c. Mutations within the mepA operator affect binding of the MepR regulatory protein and its induction by MepA substrates in Staphylococcus aureus. J. Bacteriol.197, 1104–1114.
75. Schito, G.C. 2006. The importance of the development of antibiotic resistance in Staphylococcus aureus. Clin. Microbiol. Infect. 12 Suppl 1, 3–8.
76. Schmitz, F.J., Hertel, B., Hofmann, B., Scheuring, S., Verhoef, J., Fluit, A.C., Heinz, H.P., Kohrer, K., and Jones, M.E. 1998. Relationship between mutations in the coding and promoter regions of the norA genes in 42 unrelated clinical isolates of Staphylococcus aureus and the MICs of norfloxacin for these strains. J. Antimicrob. Chemother.42, 561–563.
77. Schrader-Fischer, G. and Berger-Bachi, B. 2001. The AbcA transporter of Staphylococcus aureus affects cell autolysis. Antimicrob. Agents Chemother.45, 407–412.
78. Song, J.H., Hsueh, P.R., Chung, D.R., Ko, K.S., Kang, C.I., Peck, K.R., Yeom, J.S., Kim, S.W., Chang, H.H., Kim, Y.S., et al. 2011. Spread of methicillin-resistant Staphylococcus aureus between the community and the hospitals in Asian countries: An ANSORP study. J. Antimicrob. Chemother.66, 1061–1069.
79. Stryjewski, M.E. and Corey, G.R. 2014. Methicillin-resistant Staphylococcus aureus: An evolving pathogen. Clin. Infect. Dis. 58 Suppl 1, S10–19.
80. Tennent, J.M., Lyon, B.R., Gillespie, M.T., May, J.W., and Skurray, R.A. 1985. Cloning and expression of Staphylococcus aureus plasmid-mediated quaternary ammonium resistance in Escherichia coli. Antimicrob. Agents Chemother.27, 79–83.
81. Tennent, J.M., Lyon, B.R., Midgley, M., Jones, I.G., Purewal, A.S., and Skurray, R.A. 1989. Physical and biochemical characterization of the qacA gene encoding antiseptic and disinfectant resistance in Staphylococcus aureus. J. Gen. Microbiol.135, 1–10.
82. Truong-Bolduc, Q.C., Dunman, P.M., Eidem, T., and Hooper, D.C. 2011. Transcriptional profiling analysis of the global regulator NorG, a GntR-like protein of Staphylococcus aureus. J. Bacteriol.193, 6207–6214.
83. Truong-Bolduc, Q.C. and Hooper, D.C. 2007. The transcriptional regulators NorG and MgrA modulate resistance to both quinolones and beta-lactams in Staphylococcus aureus. J. Bacteriol.189, 2996–3005.
84. Truong-Bolduc, Q.C. and Hooper, D.C. 2010. Phosphorylation of MgrA and its effect on expression of the NorA and NorB efflux pumps of Staphylococcus aureus. J. Bacteriol.192, 2525–2534.
85. Truong-Bolduc, Q.C., Strahilevitz, J., and Hooper, D.C. 2006. NorC, a new efflux pump regulated by MgrG of Staphylococcus aureus. Antimicrob. Agents Chemother.50, 1104–1107.
86. Truong-Bolduc, Q.C., Villet, R.A., Estabrooks, Z.A., and Hooper, D.C. 2014. Native efflux pumps contribute resistance to antimicrobials of skin and the ability of Staphylococcus aureus to colonize skin. J. Infect. Dis.209, 1485–1493.
87. Truong-Bolduc, Q.C., Zhang, X., and Hooper, D.C. 2003. Characterization of NorR protein, a multifunctional regulator of NorA expression in Staphylococcus aureus. J. Bacteriol.185, 3127–3138.
88. xTynecka, Z., Gos, Z., and Zajac, J. 1981. Reduced cadmium transport determined by a resistance plasmid in Staphylococcus aureus. J. Bacteriol.147, 305–312.
89. Ubukata, K., Itoh-Yamashita, N., and Konno, M. 1989. Cloning and expression of the norA gene for fluoroquinolone resistance in Staphylococcus aureus. Antimicrob. Agents Chemother.33. 1535–1539.
90. United States Centers for Disease Control and Prevention. 2013. Antibiotic resistance threats in the united states. 2013. Report.
91. van Bijnen, E.M., Paget, W.J., den Heijer, C.D., Stobberingh, E.E., Bruggeman, C.A., Schellevis, F.G., and Team, A.S. 2014. Primary care treatment guidelines for skin infections in europe: Congruence with antimicrobial resistance found in commensal Staphylococcus aureus in the community. BMC Family Practice15. 175.
92. Van Boeckel, T.P., Gandra, S., Ashok, A., Caudron, Q., Grenfell, B.T., Levin, S.A., and Laxminarayan, R. 2014. Global antibiotic consumption 2000 t. 2010. An analysis of national pharmaceutical sales data. Lancet Infect. Dis.14, 742–750.
93. Velamakanni, S., Yao, Y., Gutmann, D.A., and van Veen, H.W. 2008. Multidrug transport by the ABC transporter Sav1866 from Staphylococcus aureus. Biochemistry47, 9300–9308.
94. Villet, R.A., Truong-Bolduc, Q.C., Wang, Y., Estabrooks, Z., Medeiros, H., and Hooper, D.C. 2014. Regulation of expression of abcA and its response to environmental conditions. J. Bacteriol.196, 1532–1539.
95. Wassenaar, T.M., Ussery, D., Nielsen, L.N., and Ingmer, H. 2015. Review and phylogenetic analysis of qac genes that reduce susceptibility to quaternary ammonium compounds in Staphylococcus species. Eur. J. Microbiol. Immunol. (Bp).5, 44–61.
96. Webber, M.A. and Piddock, L.J. 2003. The importance of efflux pumps in bacterial antibiotic resistance. J. Antimicrob. Chemother.51, 9–11.
97. WHO. 2002. Prevention of hospital-acquired infections. WHO. 2014. Antimicrobial resistance global report on surveillance. Report.
98. Williamson, D.A., Coombs, G.W., and Nimmo, G.R. 2014. Staphylococcus aureus ‘down under’: Contemporary epidemiology of S. aureus in australia, new zealand, and the south west pacific. Clin. Microbiol. Infect.20, 597–604.
99. Yamada, Y., Hideka, K., Shiota, S., Kuroda, T., and Tsuchiya, T. 2006a. Gene cloning and characterization of SdrM, a chromosomally-encoded multidrug efflux pump, from Staphylococcus aureus. Biol. Pharm. Bull.29, 554–556.
100. Yamada, Y., Shiota, S., Mizushima, T., Kuroda, T., and Tsuchiya, T. 2006b. Functional gene cloning and characterization of MdeA, a multidrug efflux pump from Staphylococcus aureus. Biol. Pharm. Bull.29, 801–804.
101. Yan, N. 2013. Structural advances for the major facilitator superfamily (MFS) transporters. Trends Biochem. Sci.38, 151–159.
102. Yoshikai, H., Kizaki, H., Saito, Y., Omae, Y., Sekimizu, K., and Kaito, C. 2015. Multidrug-resistance transporter AbcA secretes Staphylococcus aureus cytolytic toxins. J. Infect. Dis. doi: 10.1093/infdis/jiv376.