Chapter 66 : Mechanisms of Resistance to Antibacterial Agents

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Antimicrobial resistance arises by (i) mutation of cellular genes, (ii) acquisition of exogenous resistance genes, or (iii) mutation of acquired genes. The most completely studied example of regulatory mutation resulting in resistance is the derepression of the chromosomal β-lactamase of spp. As bacteria have responded to the challenge of antimicrobial agents, so have researchers responded to the challenge of antibiotic resistance. The majority of pumps that extrude one or more antibiotic classes from the bacterial cell are located in the cytoplasmic membrane and use proton motive force to drive drug efflux. This chapter describes resistance mechanisms for different antimicrbial classes. In explaining resistance to aminoglycosides (amikacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, streptomycin, and tobramycin), the chapter explains how aminoglycosides reach their target in bacterial cells and then reviews their mechanism of action. The clinical indications for aminoglycoside therapy are also summarized in the chapter. Resistance to aminoglycosides can occur by four mechanisms: (i) loss of cell permeability (decreased uptake), (ii) alterations in the ribosome that prevent binding, (iii) expulsion by efflux pumps, and (iv) enzymatic inactivation by aminoglycoside-modifying enzymes (AMEs). The most common mechanism of resistance to chloramphenicol is the elaboration of CATs. The antibiotics nitrofurazone and nitrofurantoin are used in the treatment of genitourinary infections and as topical antibacterial agents. The ultimate importance of efflux pump activations for clinical resistance to tigecycline awaits more extensive clinical use.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66

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Bacterial Proteins
Antibacterial Agents
Small Multidrug Resistance Family
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Image of FIGURE 1

Serine β-lactamases and their reactions with β-lactam carbonyl donors. Modified from reference .

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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Image of FIGURE 2

Representation of the crystal structure of the AcrAΒ-TolC three-component RND multidrug efflux pump. On the left are the three components of the pumps as they link the cytoplasmic (inner) membrane to the outer membrane. The periplasmic linker protein (AcrA) is shown only in outline to allow visualization of the linkage between AcrB and TolC. On the right, an outline of the pump shown at the left is presented, detailing the functional regions of the pump. Reprinted with permission from reference 182.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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Image of FIGURE 3

Sites of modification on kanamycin B by various AMEs. The arrows point to the sites of modification by the specific enzymes, namely, acetyltransferases, phosphotransferases, and nucleotidyltransferases. Reprinted with permission from reference 145.

Citation: Rice L, Bonomo R. 2011. Mechanisms of Resistance to Antibacterial Agents, p 1082-1114. In Versalovic J, Carroll K, Funke G, Jorgensen J, Landry M, Warnock D (ed), Manual of Clinical Microbiology, 10th Edition. ASM Press, Washington, DC. doi: 10.1128/9781555816728.ch66
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1. Adams, M. D.,, G. C. Nickel,, S. Bajaksouzian,, H. Lavender,, A. R. Murthy,, M. R. Jacobs,, and R. A. Bonomo. 2009. Resistance to colistin in Acinetobacter baumannii associated with mutations in the PmrAB two-component syste. Antimicrob. Agents Chemother. 53:36283634.
2. Adcock, P. M.,, P. Pastor,, F. Medley,, J. E. Patterson,, and T. V. Murphy. 1998. Methicillin-resistant Staphylococcus aureus in two child care center. J. Infect. Di. 178:577580.
3. Aires, J. R.,, and H. Nikaido. 2005. Aminoglycosides are captured from both periplasm and cytoplasm by the AcrD multidrug efflux transporter of Escherichia coli. J. Bacteriol. 187:19231929.
4. Alekshun, M. N.,, and S. B. Levy. 1997. Regulation of chromosomally mediated multiple antibiotic resistance: the mar regulo. Antimicrob. Agents Chemother. 41:20672075.
5. Alksne, L. E.,, and B. A. Rasmussen. 1997. Expression of the AsbAl, OXA-12, and AsbMl β-lactamases in Aeromonas jandaei AER 14 is coordinated by a two-component regulo. J. Bacteriol. 179:20062013.
6. Alovero, F. L.,, X. S. Pan,, J. E. Morris,, R. H. Manzo,, and L. M. Fisher. 2000. Engineering the specificity of antibacterial fluoroquinolones: benzenesulfonamide modifications at C-7 of ciprofloxacin change its primary target in Streptococcus pneumoniae from topoisomerase IV to gyras. Antimicrob. Agents Chemother. 44:320325.
7. Amoroso, A.,, D. Demares,, M. Mollerach,, G. Gutkind,, and J. Coyette. 2001. All detectable high-molecular-mass penicillin-binding proteins are modified in a high-level (β-lactam-resistant clinical isolate of Streptococcus mitis. Antimicrob. Agents Chemother. 45:20752081.
8. Arbeloa, A.,, J. E. Hugonnet,, A. C. Sentilhes,, N. Josseaume,, L. Dubost,, C. Monsempes,, D. Blanot,, J. P. Brouard,, and M. Arthur. 2004. Synthesis of mosaic peptidoglycan cross-bridges by hybrid peptidoglycan assembly pathways in gram-positive bacteri. J. Biol. Che. 279:4154641556.
9. Arbeloa, A.,, H. Segal,, J. E. Hugonnet,, N. Josseaume,, L. Dubost,, J. P. Brouard,, L. Gutmann,, D. Mengin-Lecreulx,, and M. Arthur. 2004. Role of class A penicillin-binding proteins in PBP5-mediated (J-lactam resistance in Enterococcus faecalis. J. Bacteriol. 186:12211228.
10. Arias, C. A.,, M. Vallejo,, J. Reyes,, D. Panesso,, J. Moreno,, E. Castaneda,, M. V. Villegas,, B. E. Murray,, and J. P. Quinn. 2008. Clinical and microbiological aspects of linezolid resistance mediated by the cfr gene encoding a 23S rRNA methyltransferas. J. Clin. Microbiol. 46:892896.
11. Arthur, M.,, F. Depardieu,, C. Molinas,, P. Reynolds,, and P. Courvalin. 1995. The vanZ gene of Tnl546 from Enterococcus faecium BM4147 confers resistance to teicoplani. Gen. 154:8792.
12. Arthur, M.,, C. Molinas,, and P. Courvalin. 1992. Sequence of the vanY gene required for production of a vancomycin-inducible D,D-carboxypeptidase in Enterococcus faecium BM414. Gen. 120:111114.
13. Arthur, M.,, C. Molinas,, and P. Courvalin. 1992. The VanS-VanR two-component regulatory system controls synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium 414. J. Bacterio. 174:25822591.
14. Arthur, M.,, C. Molinas,, F. Depardieu,, and P. Courvalin. 1993. Characterization of Tnl546, a Tn3-related transposon conferring glycopeptide resistance by synthesis of depsipeptide peptidoglycan precursors in Enterococcus faecium BM414. J. Bacterio. 175:117127.
15. Arthur, M.,, P. Reynolds,, and P. Courvalin. 1996. Glycopeptide resistance in enterococc. Trends Microbiol. 4:401407.
16. Aslangul, E.,, M. Baptista,, B. Fantin,, F. Depardieu,, M. Arthur,, P. Courvalin,, and C. Carbon. 1997. Selection of glycopeptide-resistant mutants of VanB-type Enterococcus faecalis BM4281 in vitro and in experimental endocarditi. J. Infect. Di. 175:598605.
17. Azucena, E.,, and S. Mobashery. 2001. Aminoglycoside-modifying enzymes: mechanisms of catalytic processes and inhibitio. Drag Resist. Update. 4:106117.
18. Balfour, J. A.,, and D. P. Figgitt. 2001. Telithromyci. Drag. 61:815829.
19. Barcus, V. A.,, K. Ghanekar,, M. Yeo,, T. J. Coffey,, and C. G. Dowson. 1995. Genetics of high level penicillin resistance in clinical isolates of Streptococcus pneumoniae.. FEMS Microbiol. Let. 126:299303.
20. Beaman, T. W.,, M. Sugantino,, and S. L. Roderick. 1998. Structure of the hexapeptide xenobiotic acetyltransferase from Pseudomonas aeruginosa. Biochemistr. (Moscow) 37:66896696.
21. Belcheva, A.,, and D. Golemi-Kotra. 2008. A close-up view of the VraSR two-component system. A mediator of Staphylococcus aureus response to cell wall damag. J. Biol. Che. 283:1235412364.
22. Billot-Klein, D.,, L. Gutmann,, D. Bryant,, D. Bell,, J. van Heijenoort,, J. Grewal,, and D. M. Shlaes. 1996. Peptidoglycan synthesis and structure in Staphylococcus haemolyticus expressing increasing levels of resistance to glycopeptide antibiotic. J. Bacterio. 178:46961703.
23. Bissonnette, L.,, S. Champetier,, J. P. Buisson,, and P. H. Roy. 1991. Characterization of the nonenzymatic chloram-phenicol resistance (cmlA) gene of the In-4 integron of Tnl696: similarity of the product to transmembrane transport protein. J. Bacterio. 173:44934502.
24. Bjorkman, J.,, I. Nagaev,, O. G. Berg,, D. Hughes,, and D. I. Andersson. 2000. Effects of environment on compensatory mutations to ameliorate costs of antibiotic resistanc. Scienc. 287:14791482.
25. Blanche, F.,, B. Cameron,, F. X. Bernard,, L. Maton,, B. Manse,, L. Ferrero,, N. Ratet,, C. Lecoq,, A. Goniot,, D. Bisch,, and J. Crouzet. 1996. Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerase. Antimicrob. Agents Chemother. 40:27142720.
26. Bolton, L. R.,, L. C. Kelley,, M. D. Lee,, P. J. Fedorka-Cray,, and J. J. Maurer. 1999. Detection of multidrug-resistant Salmonella enterica serotype Typhimurium DTI 04 based on a gene which confers cross-resistance to florfenicol and chloramphenico. J. Clin. Microbiol. 37:13481351.
27. Bonnet, R. 2004. Growing group of extended-spectrum f5-lactamases: the CTX-M enzyme. Antimicrob. Agents Chemother. 48:114
28. Bonomo, R. A.,, C. G. Dawes,, J. R. Knox,, and D. M. Shlaes. 1995. β-Lactamase mutations far from the active site influence inhibitor bindin. Biochim. Biophys. Act. 1247:121125.
29. Bou, G.,, A. Oliver,, and J. Martinez-Beltran. 2000. OXA-24, a novel class D (β-lactamase with carbapenemase activity in an Acinetobacter baumannii clinical strai. Antimicrob. Agents Chemother. 44:15561561.
30. Bradford, P. A. 2001. Extended-spectrum (β-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threa. Clin. Microbiol. Re. 14:933951.
31. Bradford, P. A. 2001. What's new in beta-lactamases. Curr. Infect. Dis. Re. 3:1319.
32. Bradford, P. A.,, C. Urban,, N. Mariano,, S. J. Projan,, J. J. Rahal,, and K. Bush. 1997. Imipenem resistance in Klebsiella pneumoniae is associated with the combination of ACT-1, a plasmid-mediated AmpC (β-lactamase, and the loss of an outer membrane protei. Antimicrob. Agents Chemother. 41:563569.
33. Bratu, S.,, M. Mooty,, S. Nichani,, D. Landman,, C. Gullans,, B. Pettinato,, U. Karumudi,, P. Tolaney,, and J. Quale. 2005. Emergence of KPC-possessing Klebsiella pneumordae in Brooklyn, New York: epidemiology and recommendations for detectio. Antimicrob. Agents Chemother. 49:30183020.
34. Brown, N. G.,, S. Shanker,, B. V. Venkataram Prasad,, and T. Palzkill. 2009. Structural and biochemical evidence that a TEM-1 β-lactamase N170G active site mutant acts via substrate-assisted catalysi. J. Biol. Chem. 284:3370333712.
35. Bruand, C.,, L. Chatelier,, S. D. Ehrlich,, and L. Janniere. 1993. A fourth class of theta-replicating plasmids: the Pamβ1 family from Gram-positive bacteri. Proc. Natl. Acad. Sci. US. 90:1166811672.
35a. Bush, K.,, and G. A. Jacoby. 2010. Updated functional classification of (β-lactamase. Antimicrob. Agents Chemother. 54:969976.
36. Bush, K.,, G. A. Jacoby,, and A. A. Medeiros. 1995. A functional classification scheme for (β-lactamases and its correlation with molecular structur. Antimicrob. Agents Chemothe. 39:12111233.
37. Camargo, I. L.,, H. M. Neoh,, L. Cui,, and K. Hiramatsu. 2008. Serial daptomycin selection generates daptomycin-nonsusceptible Staphylococcus aureus strains with a heterogeneous vancomycin-intermediate phenotyp. Antimicrob. Agents Chemothe. 52:42891299.
38. Campbell, B. D.,, and R. J. Kadner. 1980. Relation of aerobiosis and ionic strength to the uptake of dihydrostreptomycin in Escherichia coli.. Biochim. Biophys. Act. 593:110.
39. Carfi, A.,, S. Pares,, E. Duee,, M. Galleni,, C. Duez,, J. M. Frere,, and O. Dideberg. 1995. The 3-D structure of a zinc metallo-β-lactamase from Bacillus cereus reveals a new type of protein fol. EMBO. 14:49141921.
40. Carias, L. L.,, S. D. Rudin,, C. J. Donskey,, and L. B. Rice. 1998. Genetic linkage and cotransfer of a novel, vanB-containing transposon (Tn5382) and a low-affinity penicillin-binding protein 5 gene in a clinical vancomycin-resistant Enterococcus faecium isolat. J. Bacteria. 180:44264434-
41. Carlier, J. P.,, N. Sellier,, M. N. Rager,, and G. Reysset. 1997. Metabolism of a 5-nitroimidazole in susceptible and resistant isogenic strains of Bacteroides fragilis. Antimicrob. Agents Chemothe. 41:14951499.
42. Carrer, A.,, N. Fortineau,, and P. Nordmann. 2010. Use of ChromID extended-spectrum β-lactamase medium for detecting carbapenemase-producing Enterobacteriaceae. J. Clin. Microbiol. 48:19131914.
43. Carter, A. P.,, W. M. Clemons,, D. E. Brodersen,, R. J. Morgan-Warren,, B. T. Wimberly,, and V. Ramakrishnan. 2000. Functional insights from the structure of the 30S ribosomal subunit and its interactions with antibiotic. Natur. 407:340348.
44. Casadewall, B.,, P. E. Reynolds,, and P. Courvalin. 2001. Regulation of expression of the vanD glycopeptide resistance gene cluster from Enterococcus faecium BM433. J. Bacteriol. 183:34363446.
45. Castanheira, M.,, M. A. Toleman,, R. N. Jones,, F. J. Schmidt,, and T. R. Walsh. 2004. Molecular characterization of a β-lactamase gene, blaGIM-1 encoding a new subclass of metallo-beta-lactamas. Antimicrob. Agents Chemothe. 48:46544661.
46. Cattoir, V.,, and P. Nordmann. 2009. Plasmid-mediated quinolone resistance in gram-negative bacterial species: an updat. Curr. Med. Chem. 16:10281046.
47. Chambers, H. F. 1997. Methicillin resistance in staphylococci: molecular and biochemical basis and clinical implication. Clin. Microbiol. Re. 10:781791.
48. Chang, F. Y.,, J. E. Peacock, Jr.,, D. M. Musher,, P. Triplett,, B. B. MacDonald,, J. M. Mylotte,, A. O'Donnell,, M. M. Wagener,, and V. L. Yu. 2003. Staphylococcus aureus bacteremia: recurrence and the impact of antibiotic treatment in a prospective multicenter stud. Medicin. (Baltimore) 82:333339.
49. Chen, Y.,, J. Delmas,, J. Sirot,, B. Shoichet,, and R. Bonnet. 2005. Atomic resolution structures of CTX-M beta-lactamases: extended spectrum activities from increased mobility and decreased stabilit. J. Mol. Bio. 348:349362.
50. Chen, Y.,, A. McReynolds,, and B. K. Shoichet. 2009. Re-examining the role of Lys67 in class C beta-lactamase catalysi. Protein Sci. 18:662669.
51. Chen, Y.,, G. Minasov,, T. A. Roth,, F. Prati,, and B. K. Shoichet. 2006. The deacylation mechanism of AmpC beta-lactamase at ultrahigh resolutio. J. Am. Chem. Soc. 128:29702976.
52. Chopra, I.,, and M. Roberts. 2001. Tetracycline antibiotics: mode of action, applications, molecular biology, and epidemiology of bacterial resistanc. Microbiol. Mol. Biol. Rev. 65:232260.
53. Climo, M. W.,, R. L. Patron,, and G. L. Archer. 1999. Combinations of vancomycin and β-lactams are synergistic against staphylococci with reduced susceptibilities to vancomyci. Antimicrob. Agents Chemothe. 43:17471753.
54. Concha, N. O.,, C. A. Janson,, P. Rowling,, S. Pearson,, C. A. Cheever,, B. P. Clarke,, C. Lewis,, M. Galleni,, J. M. Frere,, D. J. Payne,, J. H. Bateson,, and S. S. Abdel-Meguid. 2000. Crystal structure of the IMP-1 metallo β-lactamase from Pseudomonas aeruginosa and its complex with a mercaptocar-boxylate inhibitor: binding determinants of a potent, broad-spectrum inhibito. Biochemistr. (Moscow) 39:42884298.
55. Coronado, V. G.,, J. R. Edwards,, D. H. Culver,, and R. P. Gaynes. 1995. Ciprofloxacin resistance among nosocomial Psemiomonas aeruginosa and Staphylococcus aureus in the United States. National Nosocomial Infections Surveillance (NNIS) System. Infec. Control Hosp. Epidemio. 16:7175.
56. Couto, I.,, H. de Lencastre,, E. Severina,, W. Kloos,, J. A. Webster,, R. J. Hubner,, I. S. Sanches,, and A. Tomasz. 1996. Ubiquitous presence of a mecA homologue in natural isolates of Staphylococcus sciuri. Microb. Drug Resis. 2:377391.
57. Crichlow, G. V.,, A. P. Kuzin,, M. Nukaga,, K. Mayama,, T. Sawai,, and J. R. Knox. 1999. Structure of the extended-spectrum class C beta-lactamase of Enterobacter cloacae GC1, a natural mutant with a tandem tripeptide insertio. Biochemistr. (Moscow) 38:1025610261.
58. Crowder, M. W.,, J. Spencer,, and A. J. Vila. 2006. Metallo-beta-lactamases: novel weaponry for antibiotic resistance in bacteri. Ace. Chem. Res. 39:721728.
59. Cui, L.,, A. Iwamoto,, J. Q. Lian,, H. M. Neoh,, T. Maruyama,, Y. Horikawa,, and K. Hiramatsu. 2006. Novel mechanism of antibiotic resistance originating in vancomycin-intermediate Staphylococcus aureus. Antimicrob. Agents Chemother. 50:428438.
60. Dahl, K. H.,, E. W. Lundblad,, T. P. Rokenes,, O. Olsvik,, and A. Sundsfjord. 2000. Genetic linkage of the vanB2 gene cluster to Tn5382 in vancomycin-resistant enterococci and characterization of two novel insertion sequence. Microbiolog. 146:14691479.
61. Darini, A. L.,, M. F. Palepou,, and N. Woodford. 2000. Effects of the movement of insertion sequences on the structure of VanA glycopeptide resistance elements in Enterococcus faecium.. Antimicrob. Agents Chemothe. 44:13621364.
62. D'Costa, V. M.,, K. M. McGrann,, D. W. Hughes,, and G. D. Wright. 2006. Sampling the antibiotic resistom. Scienc. 311:374377.
63. de la Campa, A. G.,, L. Balsalobre,, C. Ardanuy,, A. Fenoll,, E. Perez-Trallero,, and J. Linares. 2004. Fluoroquinolone resistance in penicillin-resistant Streptococcus pneumoniae clones, Spain. EmCT. Infect. Dis. 10:17511759.
64. Delaire, M.,, R. Labia,, J. P. Samama,, and J. M. Masson. 1992. Site-directed mutagenesis at the active site of Escherichia coli TEM-1 beta-lactamase. Suicide inhibitor-resistant mutants reveal the role of arginine 244 and methionine 69 in catalysi. J. Biol. Che. 267:2060020606.
65. Deurenberg, R. H.,, and E. E. Stobberingh. 2008. The evolution of Staphylococcus aureus. Infect. Genet. Evol. 8:747763.
66. Docquier, J. D.,, V. Calderone,, F. De Luca,, M. Benvenuti,, F. Giuliani,, L. Bellucci,, A. Tafi,, P. Nordmann,, M. Botta,, G. M. Rossolini,, and S. Mangani. 2009. Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemase. Chem. Biol. 16:540547.
67. Doi, Y.,, B. A. Potoski,, J. M. Adams-Haduch,, H. E. Sidjabat,, A. W. Pasculle,, and D. L. Paterson. 2008. Simple disk-based method for detection of Klebsiella pneumoniae carbapenemase-type β-lactamase by use of a boronic acid compoun. J. Clin. Microbiol. 46:40831086.
68. Donskey, C. J.,, J. A. Hanrahan,, R. A. Hutton,, and L. B. Rice. 2000. Effect of parenteral antibiotic administration on establishment of colonization with vancomycin-resistant Enterococcus faetium in the mouse gastrointestinal trac. J. Infect. Dis. 181:18301833.
69. Douthwaite, S.,, L. H. Hansen,, and P. Mauvais. 2000. Macrolide-ketolide inhibition of MLS-resistant ribosomes is improved by alternative drug interaction with domain II of 23S rRN. Mol. Microbiol. 36:183193.
70. Dubois, V.,, L. Poirel,, C. Arpin,, L. Coulange,, C. Bebear,, P. Nordmann,, and C. Quentin. 2004- SHV-49, a novel inhibitor-resistant β-lactamase in a clinical isolate of Klebsiella pneumordae. Antimicrob. Agents Chemother. 48:44664469.
71. Dutka-Malen, S.,, B. Blaimont,, G. Wauters,, and P. Courvalin. 1994. Emergence of high-level resistance to glycopeptides in Enterococcus gallinarum and Enterococcus casselifiavus. Antimicrob. Agents Chemother. 38:16751677.
72. Edwards, D. I. 1993. Nitroimidazole drugs-action and resistance mechanisms. I. Mechanisms of actio. J. Antimicrob. Chemother. 31:920.
73. Edwards, D. I. 1993. Nitroimidazole drugs-action and resistance mechanisms. II. Mechanisms of resistanc. J. Antimicrob. Chemothe. 31:201210.
74. Eliopoulos, G. M.,, B. F. Farber,, B. E. Murray,, C. Wennersten,, and R. Moellering, Jr. 1984- Ribosomal resistance of clinical enterococcal isolates to streptomyci. Antimicrob. Agents Chemother. 25:398399.
75. Ena, J.,, M. M. Lopez-Perezagua,, C. Martinez-Peinado,, M. A. Cia-Barrio,, and I. Ruiz-Lopez. 1998. Emergence of ciprofloxacin resistance in Escherichia coli isolates after widespread use of fluoroquinolone. Diagn. Microbiol. Infect. Dis. 30:103107.
76. Enne, V. I.,, A. King,, D. M. Livermore,, and L. M. Hall. 2002. Sulfonamide resistance in Haemophilus influenzae mediated by acquisition of sul2 or a short insertion in chromosomal folP. Antimicrob. Agents Chemother. 46:19341939.
77. Evers, S.,, and P. Courvalin. 1996. Regulation of VanB-type vancomycin resistance gene expression by the VanSB-VanRB two-component regulatory system in Enterococcus faecalis V58. J. Bacterio. 178:13021309.
78. Evers, S.,, D. F. Sahm,, and P. Courvalin. 1993. The vanB gene of vancomycin-resistant Enterococcus faecalis V583 is structurally-related to genes encoding D-ala:D-ala ligases and glycopeptide-resistance proteins VanA and Van. Gen. 124:143144
79. Farzaneh, S.,, E. B. Chaibi,, J. Peduzzi,, M. Barthelemy,, R. Labia,, J. Blazquez,, and F. Baquero. 1996. Implication of Ile-69 and Thr-182 residues in kinetic characteristics of IRT-3 (TEM-32) β-lactamas. Antimicrob. Agents Chemother. 40:24342436.
80. Ferber, D. 2000. Antibiotic resistance. Superbugs on the hoof. Scienc. 288:792794.
81. Ferretti, J. J.,, K. S. Gilmore,, and P. Courvalin. 1986. Nucleotide sequence of the gene specifying the bifunctional 6'-aminoglycoside acetyltransferase-2" aminoglycoside phosphotransferase enzyme in Streptococcus faecalis and identification and cloning of the gene regions specifying the two activitie. J. Bacteriol. 167:631638.
82. Ferretti, J. J.,, W. M. McShan,, D. Ajdic,, D. J. Savic,, G. Savic,, K. Lyon,, C. Primeaux,, S. Sezate,, A. N. Suvorov,, S. Kenton,, H. S. Lai,, S. P. Lin,, Y. Qian,, H. G. Jia,, F. Z. Najar,, Q. Ren,, H. Zhu,, L. Song,, J. White,, X. Yuan,, S. W. Clifton,, B. A. Roe,, and R. McLaughlin. 2001. Complete genome sequence of an Ml strain of Streptococcus pyogenes. Proc. Natl. Acad. Sci. US. 98:46581663.
83. Fey, P. D.,, B. Said-Salim,, M. E. Rupp,, S. H. Hinrichs,, D. J. Boxrud,, C. C. Davis,, B. N. Kreiswirth,, and P. M. Schlievert. 2003. Comparative molecular analysis of community- or hospital-acquired methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 47:196203.
84. Fiett, J.,, A. Palucha,, B. Miaczynska,, M. Stankiewicz,, H. Przondo-Mordarska,, W. Hryniewicz,, and M. Gniadkowski. 2000. A novel complex mutant β-lactamase, TEM-68, identified in a Klebsiella pneumoniae isolate from an outbreak of extended-spectrum β-lactamase-producing klebsiella. Antimicrob. Agents Chemother. 44:14991505.
85. Filipe, S. R.,, and A. Tomasz. 2000. Inhibition of the expression of penicillin resistance in Streptococcus pneumoniae by inactivation of cell wall muropeptide branching gene. Proc. Nad. Acad. Sci. US. 97:48914896.
86. Fines, M.,, B. Perichon,, P. Reynolds,, D. F. Sahm,, and P. Courvalin. 1999. VanE, a new type of acquired glycopeptide resistance in Enterococcus faecalis BM440. Antimicrob. Agents Chemother. 43:21612164-
87. Fitton, J. E.,, and W. V. Shaw. 1979. Comparison of chloramphenicol acetyltransferase variants in staphylococci. Purification, inhibitor studies and N-terminal sequence. Biochem. J. 177:575582.
88. Fitzgerald, J. R.,, D. E. Sturdevant,, S. M. Mackie,, S. R. Gill,, and J. M. Musser. 2001. Evolutionary genomics of Staphylococcus aureus: insights into the origin of methicillin-resistant strains and the toxic shock syndrome epidemi. Proc. Natl. Acad. Sci. US. 98:88218826.
89. Flannagan, S. E.,, J. W. Chow,, S. M. Donabedian,, W. J. Brown,, M. B. Perri,, M. J. Zervos,, Y. Ozawa,, and D. B. Clewell. 2003. Plasmid content of a vancomycin-resistant Enterococcus faecalis isolate from a patient also colonized by Staphylococcus aureus with a VanA phenotyp. Antimicrob. Agents Chemother. 47:39543959.
90. Fontana, R.,, M. Aldegheri,, M. Ligozzi,, H. Lopez,, A. Sucari,, and G. Satta. 1994. Overproduction of a low-affinity penicillin-binding protein and high-level ampicillin resistance in Enterococcus faecium. Antimicrob. Agents Chemother. 38:19801983.
91. Fowler, V. G., Jr.,, H. W. Boucher,, G. R. Corey,, E. Abrutyn,, A. W. Karchmer,, M. E. Rupp,, D. P. Levine,, H. F. Chambers,, F. P. Tally,, G. A. Vigliani,, C. H. Cabell,, A. S. Link,, I. DeMeyer,, S. G. Filler,, M. Zervos,, P. Cook,, J. Parsonnet,, J. M. Bernstein,, C. S. Price,, G. N. Forrest,, G. Fatkenheuer,, M. Gareca,, S. J. Rehm,, H. R. Brodt,, A. Tice,, and S. E. Cosgrove. 2006. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N. Engl. J. Me. 355:653665.
92. France, A. M.,, K. M. Kugeler,, A. Freeman,, C. A. Za-lewski,, M. Blahna,, L. Zhang,, C. F. Marrs,, and B. Foxman. 2005. Clonal groups and the spread of resistance to trimethoprim-sulfamethoxazole in uropathogenic Escherichia coli. Chem. Infect. Dis. 40:11011107.
93. Frase, H.,, Q. Shi,, S. A. Testero,, S. Mobashery,, and S. B. Vakulenko. 2009. Mechanistic basis for the emergence of catalytic competence against carbapenem antibiotics by the GES family of beta-lactamase. J. Biol. Che. 284:2950929513.
94. Galas, D. J.,, and M. Chandler,. 1989. Bacterial insertion sequence. p. 109162. In D. E. Berg, and M. M. Howe (ed.), Mobile DNA. American Society for Microbiology, Washington, DC.
95. Galimand, M.,, P. Courvalin,, and T. Lambert. 2003. Plasmid-mediated high-level resistance to aminoglycosides in Enterobacteriaceae due to 16S rRNA methylatio. Antimicrob. Agents Chemother. 47:25652571.
96. Galimand, M.,, S. Sabtcheva,, P. Courvalin,, and T. Lambert. 2005. Worldwide disseminated armA aminoglycoside resistance methylase gene is borne by composite transposon Tnl548.. Antimicrob. Agents Chemother. 49:29492953.
97. Galleni, M.,, J. Lamotte-Brasseur,, G. M. Rossolini,, J. Spencer,, O. Dideberg,, and J. M. Frere. 2001. Standard numbering scheme for class B β-lactamase. Antimicrob. Agents Chemother. 45:660663.
98. Garau, G.,, C. Bebrone,, C. Anne,, M. Galleni,, J. M. Frere,, and O. Dideberg. 2005. A metallo-beta-lactamase enzyme in action: crystal structures of the monozinc carbapenemase CphA and its complex with biapene. J. Mol. Biol. 345:785795.
99. Gamier, F.,, S. Taourit,, P. Glaser,, P. Courvalin,, and M. Galimand. 2000. Characterization of transposon Tnl549, conferring VanB-type resistance in Enterococcus sp. Microbiolog. 146:14811489.
100. Gherman, B. F.,, S. D. Goldberg,, V. W. Cornish,, and R. A. Friesner. 2004. Mixed quantum mechanical/molecular mechanical (QM/MM) study of the deacylation reaction in a penicillin binding protein (PBP) versus in a class C beta-lactamas. J. Am. Chem. Soc. 126:76527664
101. Ghuysen, J. M. 1991. Serine β-lactamases and penicillin-binding protein. Aram. Rev. Microbiol. 45:3767.
102. Giakkoupi, P.,, O. Pappa,, M. Polemis,, A. C. Vatopoulos,, V. Miriagou,, A. Zioga,, C. C. Papagiannitsis,, and L. S. Tzouvelekis. 2009. Emerging Klebsiella pneumordae isolates coproducing KPC-2 and VIM-1 carbapenemase. Antimicrob. Agents Chemother. 53:40484050.
103. Guay, D. R. 2001. An update on the role of nitrofurans in the management of urinary tract infection. Drug. 61:353364.
104. Haas, W.,, J. Sublett,, D. Kaushal,, and E. I. Tuomanen. 2004. Revising the role of the pneumococcal vex-vnncRS locus in vancomycin toleranc. J. Bacteriol. 186:84638471.
105. Hachmann, A. B.,, E. R. Angert,, and J. D. Helmann. 2009. Genetic analysis of factors affecting susceptibility of Bacillus subtitis to daptomyci. Antimicrob. Agents Chemother. 53:15981609.
106. Hackbarth, C. J.,, and H. F. Chambers. 1993. blal and blaRl regulate β-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 37:11441149.
107. Hackbarth, C. J.,, T. Kocagoz,, S. Kocagoz,, and H. F. Chambers. 1995. Point mutations in Staphylococcus aureus PBP 2 gene affect penicillin-binding kinetics and are associated with resistanc. Antimicrob. Agents Chemother. 39:103106.
108. Hakenbeck, R.,, and J. Coyette. 1998. Resistant penicillin-binding protein. Cell. Mol. Life Sci. 54:332340.
109. Hall, R. M.,, and C. M. Collis. 1995. .obile gene cassettes and integrons: capture and spread of genes by site-specific recombination. Mol. Microbiol. 15:593600.
110. Hamilton-Miller, J. M. 1988. Reversal of activity of trimethoprim against gram-positive cocci by thymidine, thymine and ’folates.’. J. Antimicrob. Chemother. 22:3539.
111. Hayashi, T.,, K. Makino,, M. Ohnishi,, K. Kurokawa,, K. Ishii,, K. Yokoyama,, C. G. Han,, E. Ohtsubo,, K. Nakayama,, T. Murata,, M. Tanaka,, T. Tobe,, T. Iida,, H. Takami,, T. Honda,, C. Sasakawa,, N. Ogasawara,, T. Yasunaga,, S. Kuhara,, T. Shiba,, M. Hattori,, and H. Shinagawa. 2001. Complete genome sequence of enterohemorrhagic Escherichia coli 0157:H7 and genomic comparison with a laboratory strain K-1. DNA Res. 8:1122.
112. Hayden, M. K.,, G. M. Trenholm,, J. E. Schultz,, and D. F. Sahm. 1993. In vivo development of teicoplanin resistance in a VanB Enterococcus faecium isolat. J. Infect. Dis. 167:12241227.
113. Hayes, J. R.,, D. D. Wagner,, L. L. English,, L. E. Carr,, and S. W. Joseph. 2005. Distribution of streptogramin resistance determinants among Enterococcus faecium from a poultry production environment of the US. J. Antimicrob. Chemother. 55:123126.
114. Henriques Normark, B.,, R. Novak,, A. Ortqvist,, G. Kallenius,, E. Tuomanen,, and S. Normark. 2001. Clinical isolates of Streptococcus pneumordae that exhibit tolerance of vancomyci. Clin. Infect. Di. 32:552558.
115. Henze, U. U.,, and B. Berger-Bachi. 1995. Staphylococcus aureus penicillin-binding protein 4 and intrinsic β-lactam resistanc. Antimicrob. Agents Chemother. 39: 24152422.
116. Heritier, C.,, L. Poirel,, P. E. Fournier,, J. M. Claverie,, D. Raoult,, and P. Nordmann. 2005. Characterization of the naturally occurring oxacillinase of Acinetobacter baumannii. Antimicrob. Agents Chemothe. 49:4174179.
117. Heritier, C.,, L. Poirel,, T. Lambert,, and P. Nordmann. 2005. Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob. Agents Chemother. 49:31983202.
118. Hiasa, H.,, D. O. Yousef,, and K. J. Marians. 1996. DNA strand cleavage is required for replication fork arrest by a frozen topoisomerase-quinolone-DNA ternary comple. J. Biol. Che. 271:2642426429.
119. Hillen, W.,, and C. Berens. 1994. Mechanisms underlying expression of Tnl0 encoded tetracycline resistanc. Annu. Rev. Microbiol. 48:345369.
120. Hooper, D. C. 2001. Emerging mechanisms of fluoroqui-nolone resistanc. Emerg. Infect. Dis. 7:337341.
121. Hossain, A.,, M. J. Ferraro,, R. M. Pino,, R. B. Dew III,, E. S. Moland,, T. J. Lockhart,, K. S. Thomson,, R. V. Goering,, and N. D. Hanson. 2004. Plasmid-mediated carbapenem-hydrolyzing enzyme KPC-2 in an Enterobacter s. Antimicrob. Agents Chemother. 48:4438440.
122. Hughes, D. 2003. Exploiting genomics, genetics and chemistry to combat antibiotic resistanc. Nat. Rev. Gene. 4:432441.
123. Huovinen, P. 2001. Resistance to trimethoprim-sulfame-thoxazol. Clin. Infect. Dis. 32:16081614.
124. Ibuka, A.,, A. Taguchi,, M. Ishiguro,, S. Fushinobu,, Y. Ishii,, S. Kamitori,, K. Okuyama,, K. Yamaguchi,, M. Konno,, and H. Matsuzawa. 1999. Crystal structure of the E166A mutant of extended-spectrum β-lactamase Toho-1 at 1.8 Å resolutio. J. Mol. Biol. 285:20792087.
125. Ibuka, A. S.,, Y. Ishii,, M. Galleni,, M. Ishiguro,, K. Yamaguchi,, J. M. Frere,, H. Matsuzawa,, and H. Sakai. 2003. Crystal structure of extended-spectrum beta-lactamase Toho-1: insights into the molecular mechanism for catalytic reaction and substrate specificity expansio. Biochemistr. (Moscow) 42:1063410643.
126. Ito, T.,, Y. Katayama,, K. Asada,, N. Mori,, K. Tsutsumimoto,, C. Tiensasitorn,, and K. Hiramatsu. 2001. Structural comparison of three types of staphylococcal cassette chromosome mec integrated in the chromosome in methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 45: 13231336.
127. Jacobs, C.,, J.-M. Frere,, and S. Normark. 1997. Cytosolic intermediates for cell wall biosynthesis and degradation control inducible β-lactam resistance in gram-negative bacteri. Cel. 88:82332.
128. Jacobs, C.,, B. Joris,, M. Jamin,, K. Klarsov,, J. Van Beeumen,, D. Mengin-Lecreuix,, J. van Heijenoort,, J. T. van Park,, S. Normark,, and J.-M. Frère. 1995. AmpD, essential for both β-lactamase regulation and cell wall recycling, is a novel cytosolic N-acetylmuramyl-L-alanine amidas. Mol. Microbio. 15:553559.
129. Jacoby, G. A. 2009. AmpC β-lactamase. Clin. Microbiol. Re. 22:161182.
130. Jacoby, G. A. 2005. Mechanisms of resistance to quinolone. Clin. Infect. Di. 41(Suppl. 2):S120S126.
131. Jacoby, G. A.,, and A. A. Medeiros. 1991. More extended-spectrum β-lactamase. Antimicrob. Agents Chemother. 35: 16971704.
132. Jeannot, K.,, M. L. Sobel,, F. El Garch,, K. Poole,, and P. Plesiat. 2005. Induction of the MexXY efflux pump in Psemiomonas aeruginosa is dependent on drug-ribosome interactio. J. Bacteriol. 187:53415346.
133. Jones, R. N.,, T. R. Anderegg,, and J. M. Swenson. 2005. Quality control guidelines for testing gram-negative control strains with polymyxin B and colistin (polymyxin E) by standardized method. J. Clin. Microbio. 43:925927.
134. Jones, R. N.,, J. E. Ross,, M. Castanheira,, and R. E. Mendes. 2008. United States resistance surveillance results for linezolid (LEADER Program for 2007. Diagn. Microbiol. Infect. Dis. 62:416426.
135. Kaatz, G. W.,, S. M. Seo,, N. J. Dorman,, and S. A. Lerner. 1990. Emergence of teicoplanin resistance during therapy of Staphylococcus aureus endocarditi. J. Infect. Dis. 162:103108.
136. Kadurugamuwa, J. L.,, J. S. Lam,, and T. J. Beveridge. 1993. Interaction of gentamicin with the A band and B band lipopolysaccharides of Pseudomonas aeruginosa and its possible lethal effec. Antimicrob. Agents Chemother. 37:715721.
137. Katayama, Y.,, H. Murakami-Kuroda,, L. Cui,, and K. Hiramatsu. 2009. Selection of heterogeneous vancomycin-intermediate Staphylococcus aureus by imipene. Antimicrob. Agents Chemother. 53:31903196.
138. Katayama, Y.,, D. A. Robinson,, M. C. Enright,, and H. F. Chambers. 2005. Genetic background affects stability of mecA in Staphylococcus aureus. J. Clin. Microbiol. 43:23802383.
139. Kaye, K. S.,, H. S. Gold,, M. J. Schwaber,, L. Venkataraman,, Y. Qi,, P. C. De Girolami,, M. H. Samore,, G. Anderson,, J. K. Rasheed,, and F. C. Tenover. 2004. Variety of β-lactamases produced by amoxicillin-clavulanate-resistant Escherichia coli isolated in the northeastern United State. Antimicrob. Agents Chemother. 48:15201525.
140. Ke, W.,, C. R. Bethel,, J. M. Thomson,, R. A. Bonomo,, and F. van den Akker. 2007. Crystal structure of KPC-2: insights into carbapenemase activity in class A beta-lactamase. Biochemistr. (Moscow) 46:57325740.
141. Kim, J.,, Y. M. Lim,, Y. S. Jeong,, and S. Y. Seol. 2005. Occurrence of CTX-M-3, CTX-M-15, CTX-M-14, and CTX-M-9 extended-spectrum β-lactamases in Enterobacteriaceae clinical isolates in Kore. Antimicrob. Agents Chemother. 49:15721575.
142. Knox, J. R. 1995. Extended-spectrum and inhibitor-resistant TEM-type β-lactamases: mutations, specificity, and three-dimensional structur. Antimicrob. Agents Chemother. 39:25932601.
143. Ko, W. C.,, D. L. Paterson,, A. J. Sagnimeni,, D. S. Sagnimeni,, A. Von Gottberg,, S. Mohapatra,, J. M. Casellas,, H. Goossens,, L. Mulazimoglu,, G. Trenholme,, K. P. Klugman,, J. G. McCormack,, and V. L. Yu. 2002. Community-acquired Klebsiella pneumoniae bacteremia: global differences in clinical pattern. Emerg. Infect. Dis. 8:160166.
144. Kohler, T.,, M. Kok,, M. Michea-Hamzehpour,, P. Plesiat,, N. Gotoh,, T. Nishino,, L. K. Curty,, and J. C. Pechere. 1996. Multidrug efflux in intrinsic resistance to trimethoprim and sulfamethoxazole in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 40:22882290.
145. Kotra, L. P.,, J. Haddad,, and S. Mobashery. 2000. Amino-glycosides: perspectives on mechanisms of action and resistance and strategies to counter resistanc. Antimicrob. Agents Chemother. 44:32493256.
146. Lartigue, M. F.,, L. Poirel,, J. W. Decousser,, and P. Nordmann. 2005. Multidrug-resistant Shigella sonnei and Salmonella enterica serotype Typhimurium isolates producing CTX-M beta-lactamases as causes of community-acquired infection in Franc. Clin. Infect. Dis. 40:10691070.
147. Leavis, H.,, J. Top,, N. Shankar,, K. Borgen,, M. Bonten,, J. van Embden,, and R. J. Willems. 2004. A novel putative enterococcal pathogenicity island linked to the esp virulence gene of Enterococcus faecium and associated with epidemicit. J. Bacteriol. 186:672682.
148. Leavis, H. L.,, R. J. Willems,, W. J. van Wamel,, F. H. Schuren,, M. P. Caspers,, and M. J. Bonten. 2007. Insertion sequence-driven diversification creates a globally dispersed emerging multiresistant subspecies of E. faecium. PLoS Pathog. 3:e7.
149. Leclerq, R.,, S. Dutka-Malen,, A. Brisson-Noel,, C. Molinas,, E. Derlot,, M. Arthur,, J. Duval,, and P. Courvalin. 1992. Resistance of enterococci to aminoglycosides and glycopeptide. Clin. Infect. Di. 15:495501.
150. Lee, A.,, W. Mao,, M. S. Warren,, A. Mistry,, K. Hoshino,, R. Okumura,, H. Ishida,, and O. Lomovskaya. 2000. Interplay between efflux pumps may provide either additive or multiplicative effects on drug resistanc. J. Bacteriol. 182:31423150.
151. Lee, E. H.,, M. H. Nicolas,, M. D. Kitzis,, G. Pialoux,, E. Collatz,, and L. Gutmann. 1991. Association of two resistance mechanisms in a clinical isolate of Enterobacter cloacae with high-level resistance to imipene. Antimicrob. Agents Chemother. 35:10931098.
152. Leiros, H. K.,, S. Kozielski-Stuhrmann,, U. Kapp,, L. Terradot,, G. A. Leonard,, and S. M. McSweeney. 2004. Structural basis of 5-nitroimidazole antibiotic resistance: the crystal structure of NimA from Deinococcus radiodurans. J. Biol. Chem. 279:5584055849.
153. Leitsch, D.,, D. Kolarich,, M. Binder,, J. Stadlmann,, F. Altmann,, and M. Duchene. 2009. Trichomonas vaginalis: metronidazole and other nitroimidazole drugs are reduced by the flavin enzyme thioredoxin reductase and disrupt the cellular redox system. Implications for nitroimidazole toxicity and resistanc. Mol. Microbiol. 72:518536.
154. Levine, D. P.,, B. S. Fromm,, and B. R. Reddy. 1991. Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditi. Ann. Intern. Med. 115:674680.
155. Levy, S. B.,, L. M. McMurry,, T. M. Barbosa,, V. Burdett,, P. Courvalin,, W. Hillen,, M. C. Roberts,, J. I. Rood,, and D. E. Taylor. 1999. Nomenclature for new tetracycline resistance determinant. Antimicrob. Agents Chemother. 43:15231524.
156. Linares, J. 2001. The VISA/GISA problem: therapeutic implication. Clin. Microbiol. Infect. 7:815.
157. Livermore, D. M. 1992. Interplay of impermeability and chromosomal β-lactamase activity in imipenem-resistant Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 36: 20462048.
158. Livermore, D. M.,, D. F. Brown,, J. P. Quinn,, Y. Carmeli,, D. L. Paterson,, and V. L. Yu. 2004. Should third-generation cephalosporins be avoided against AmpC-inducible Enterobacteriaceae. Clin. Microbiol. Infect. 10:8485.
159. Lobkovsky, E.,, E. M. Billings,, P. C. Moews,, J. Rahil,, R. F. Pratt,, and J. R. Knox. 1994. Crystallographic structure of a phosphonate derivative of the Enterobacter cloacae P99 cephalosporinase: mechanistic interpretation of a beta-lactamase transition-state analo. Biochemistr. (Moscow) 33:67626772.
160. Lobkovsky, E.,, P. C. Moews,, H. Liu,, H. Zhao,, J. M. Frere,, and J. R. Knox. 1993. Evolution of an enzyme activity: crystallographic structure at 2-Å resolution of cephalosporinase from the ampC gene of Enterobacter cloacae P99 and comparison with a class A penicillinas. Proc. Nad. Acad. Sci. US. 90:1125711261.
161. Lobritz, M.,, R. Hutton-Thomas,, S. Marshall,, and L. B. Rice. 2003. Recombination proficiency influences frequency and locus of mutational resistance to linezolid in Enterococcus faecalis. Antimicrob. Agents Chemother. 47:33183320.
162. Magnet, S.,, P. Courvalin,, and T. Lambert. 2001. Resistance-nodulation-cell division-type efflux pump involved in aminoglycoside resistance in Acinetobacter baumannii strain BM445. Antimicrob. Agents Chemother. 45:33753380.
163. Manges, A. R.,, J. R. Johnson,, B. Foxman,, T. T. O'Bryan,, K. E. Fullerton,, and L. W. Riley. 2001. Widespread distribution of urinary tract infections caused by a multidrug-resistant Escherichia coli clonal grou. N. Engl. J. Me. 345:10071013.
164. Mao, W.,, M. S. Warren,, A. Lee,, A. Mistry,, and O. Lomovskaya. 2001. MexXY-OprM efflux pump is required for antagonism of aminoglycosides by divalent cations in Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 45:20012007.
165. Marchand, I.,, L. Damier-Piolle,, P. Courvalin,, and T. Lambert. 2004. Expression of the RND-type efflux pump Ad-eABC in Acinetobacter baumannii is regulated by the AdeRS two-component syste. Antimicrob. Agents Chemother. 48:32983304.
166. Marshall, S. H.,, C. J. Donskey,, R. Hutton-Thomas,, R. A. Salata,, and L. B. Rice. 2002. Gene dosage and linezolid resistance in Enterococcus faecium and Enterococcus faecalis. Antimicrob. Agents Chemother. 46:33343336.
167. Martinez, J. L.,, A. Alonso,, J. M. Gomez-Gomez,, and F. Baquero. 1998. Quinolone resistance by mutations in chromosomal gyrase genes. Just the tip of the iceberg. J. Antimicrob. Chemothe. 42:683688.
168. Martinez-Martinez, L.,, S. Hernandez-Alles,, S. Alberti,, J. M. Tomas,, V. J. Benedi,, and G. A. Jacoby. 1996. In vivo selection of porin-deficient mutants of Klebsiella pneumordae with increased resistance to cefoxitin and expanded-spectrum cephalosporin. Antimicrob. Agents Chemother. 40:342348.
169. Maseda, H.,, H. Yoneyama,, and T. Nakae. 2000. Assignment of the substrate-selective subunits of the MexEF-OprN multidrug efflux pump of Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 44:658664.
170. Matagne, A.,, J. Lamotte-Brasseur,, and J. M. Frere. 1998. Catalytic properties of class A beta-lactamases: efficiency and diversit. Biochem. J. 330:581598.
171. Maus, C. E.,, B. B. Plikaytis,, and T. M. Shinnick. 2005. Molecular analysis of cross-resistance to capreomycin, kanamycin, amikacin, and viomycin in Mycobacterium tuberculosis. Antimicrob. Agents Chemother. 49:31923197.
172. Maveyraud, L.,, D. Golemi,, L. P. Kotra,, S. Tranier,, S. Vakulenko,, S. Mobashery,, and J. P. Samama. 2000. Insights into class D beta-lactamases are revealed by the crystal structure of the OXA10 enzyme from Pseudomonas aeruginosa. Structure Fold Des. 8:12891298.
173. McOsker, C. C.,, and P. M. Fitzpatrick. 1994. Nitro-furantoin: mechanism of action and implications for resistance development in common uropathogens. J. Antimicrob. Chemother. 33(Suppl. A):2330.
174. Meroueh, S. O.,, J. F. Fisher,, H. B. Schlegel,, and S. Mobashery. 2005. Ab initio QM/MM study of class A beta-lactamase acylation: dual participation of Glul66 and Lys73 in a concerted base promotion of Ser7. J. Am. Chem. Soc. 127:1539715407.
175. Minasov, G.,, X. Wang,, and B. K. Shoichet. 2002. An ultra-high resolution structure of TEM-1 beta-lactamase suggests a role for Glul66 as the general base in acylatio. J. Am. Chem. Soc. 124:53335340.
176. Mingeot-Leclercq, M. P.,, Y. Glupczynski,, and P. M. Tulkens. 1999. Aminoglycosides: activity and resistanc. Antimicrob. Agents Chemother. 43:727737.
177. Miriagou, V.,, L. S. Tzouvelekis,, S. Rossiter,, E. Tzelepi,, F. J. Angulo,, and J. M. Whichard. 2003. Imipenem resistance in a Salmonella clinical strain due to plasmid-mediated class A carbapenemase KPC-. Antimicrob. Agents Chemother. 47:12971300.
178. Mishra, N. N.,, S. J. Yang,, A. Sawa,, A. Rubio,, C. C. Nast,, M. R. Yeaman,, and A. S. Bayer. 2009. Analysis of cell membrane characteristics of in vitro-selected daptomycin-resistant strains of methicillin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53:23122318.
179. Moellering, R. C.,, and A. N. Weinberg. 1971. Studies on antibiotic synergism against enterococci. II. Effect of various antibiotics on the uptake of 14C-labelled streptomycin by enterococci. J. Clin. Investig. 50:25802584.
180. Morais Cabral, J. H.,, A. P. Jackson,, C. V. Smith,, N. Shikotra,, A. Maxwell,, and R. C. Liddington. 1997. Crystal structure of the breakage-reunion domain of DNA gyras. Natur. 388:903906.
181. Murakami, K.,, and A. Tomasz. 1989. Involvement of multiple genetic determinants in high-level methicillin resistance in Staphylococcus aureus. J. Bacteriol. 171:874879.
182. Murakami, S.,, R. Nakashima,, E. Yamashita,, and A. Yamaguchi. 2002. Crystal structure of bacterial multidrug efflux transporter Acr. Natur. 419:587593.
183. Murray, I. A.,, J. V. Martinez-Suarez,, T. J. Close,, and W. V. Shaw. 1990. Nucleotide sequences of genes encoding the type II chloramphenicol acetyltransferases of Escherichia coli and Haemophilus influenzae, which are sensitive to inhibition by thiol-reactive reagent. Biochem. J. 272:505510.
184. Murray, I. A.,, and W. V. Shaw. 1997. O-Acetyltransferases for chloramphenicol and other natural product. Antimicrob. Agents Chemothe. 41:16.
185. Muthaiyan, A.,, J. A. Silverman,, R. K. Jayaswal,, and B. J. Wilkinson. 2008. Transcriptional profiling reveals that daptomycin induces the Staphylococcus aureus cell wall stress stimulon and genes responsive to membrane depolarizatio. Antimicrob. Agents Chemother. 52:980990.
186. Naas, T.,, and P. Nordmann. 1994. Analysis of a carbapenem-hydrolyzing class A beta-lactamase from Enterobacter cloacae and of its LysR-type regulatory protei. Proc. Nad. Acad. Sci. US. 91:76937697.
187. Naas, T.,, and P. Nordmann. 1999. OXA-type beta-lactamase. Curr. Pharm. Des. 5:865879.
188. Navia, M. M.,, J. Ruiz,, and J. Vila. 2002. Characterization of an integron carrying a new class D beta-lactamase (OXA-37) in Acinetobacter baumannii. Microb. Drag Resist. 8:261265.
189. Navia, M. M.,, J. Ruiz,, and J. Vila. 2004. Molecular characterization of the integrons in Shigella strains isolated from patients with traveler's diarrhe. Diagn. Microbiol. Infect. Dis. 48:175179.
190. Neuwirth, C.,, S. Madec,, E. Siebor,, A. Pechinot,, J. M. Duez,, M. Pruneaux,, M. Fouchereau-Peron,, A. Kazmierczak,, and R. Labia. 2001. TEM-89 β-lactamase produced by a Proteus mirabilis clinical isolate: new complex mutant (CMT 3) with mutations in both TEM-59 (IRT-17) and TEM-3. Antimicrob. Agents Chemother. 45:35913594.
191. Nikaido, H. 1998. Multiple antibiotic resistance and efflu. Curr. Opin. Microbiol. 1:516523.
192. Nikaido, H.,, and D. G. Thanassi. 1993. Penetration of lipophilic agents with multiple protonation sites into bacterial cells: tetracyclines and fluoroquinolones as example. Antimicrob. Agents Chemother. 37:13931399.
193. Noble, W. C.,, Z. Virani,, and R. G. A. Gee. 1992. Co-transfer of vancomycin and other resistance genes from Enterococcus faecalis NCTC 12201 to Staphylococcus aureus.. FEMS. Microbiol. Lett. 93:195198.
194. Nordmann, P.,, S. Mariotte,, T. Naas,, R. Labia,, and M. H. Nicolas. 1993. Biochemical properties of a carbapenem-hydrolyzing β-lactamase from Enterobacter cloacae and cloning of the gene into Escherichia coli. Antimicrob. Agents Chemother. 37:939946.
195. Nordmann, P.,, and L. Poirel. 2005. Emergence of plasmid-mediated resistance to quinolones in Enterobacteriaceae. J. Antimicrob. Chemother. 56:463469.
196. Nukaga, M.,, K. Mayama,, A. M. Hujer,, R. A. Bonomo,, and J. R. Knox. 2003. Ultrahigh resolution structure of a class A beta-lactamase: on the mechanism and specificity of the extended-spectrum SHV-2 enzym. J. Mol. Bio. 328:289301.
197. Oefner, C.,, A. D'Arcy,, J. J. Daly,, K. Gubernator,, R. L. Charnas,, I. Heinze,, C. Hubschwerlen,, and F. K. Winkler. 1990. Refined crystal structure of beta-lactamase from Citrobacter freundii indicates a mechanism for beta-lactam hydrolysi. Natur. 343:284288.
198. Oggioni, M. R.,, C. G. Dowson,, J. M. Smith,, R. Prowedi,, and G. Pozzi. 1996. The tetracycline resistance gene tet(M) exhibits mosaic structur. Plasmi. 35:156163.
199. Olson, A. B.,, M. Silverman,, D. A. Boyd,, A. McGeer,, B. M. Willey,, V. Pong-Porter,, N. Daneman,, and M. R. Mulvey. 2005. Identification of a progenitor of the CTX-M-9 group of extended-spectrum β-lactamases from Kluyvera georgiana isolated in Guyan. Antimicrob. Agents Chemother. 49:21122115.
200. Orencia, M. C.,, J. S. Yoon,, J. E. Ness,, W. P. Stemmer,, and R. C. Stevens. 2001. Predicting the emergence of antibiotic resistance by directed evolution and structural analysi. Nat. Struct. Biol. 8:238242.
201. Paetzel, M.,, F. Danel,, L. de Castro,, S. C. Mosimann,, M. G. Page,, and N. C. Strynadka. 2000. Crystal structure of the class D beta-lactamase OXA-1. Nat. Struct. Bio. 7:918925.
202. Pan, X. S.,, and L. M. Fisher. 1999. Streptococcus pneumoniae DNA gyrase and topoisomerase IV: overexpression, purification, and differential inhibition by fluoroquinolone. Antimicrob. Agents Chemother. 43:11291136.
203. Paterson, D. L. 2001. Extended-spectrum beta-lactamases: the European experienc. Curr. Opin. Infect. Dis. 14:697701.
204. Paterson, D. L.,, K. M. Hujer,, A. M. Hujer,, B. Yeiser,, M. D. Bonomo,, L. B. Rice,, and R. A. Bonomo. 2003. Extended-spectrum β-lactamases in Klebsiella pneumoniae bloodstream isolates from seven countries: dominance and widespread prevalence of SHV- and CTX-M-type β-lactamase. Antimicrob. Agents Chemother. 47:35543560.
205. Paterson, D. L.,, W. C. Ko,, A. Von Gottberg,, S. Mohapatra,, J. M. Casellas,, H. Goossens,, L. Mulazimoglu,, G. Trenholme,, K. P. Klugman,, R. A. Bonomo,, L. B. Rice,, M. M. Wagener,, J. G. McCormack,, and V. L. Yu. 2004. Antibiotic therapy for Klebsiella pneumoniae bacteremia: implications of production of extended-spectrum beta-lactamase. Clin. Infect. Di. 39:3137.
206. Paterson, D. L.,, W. C. Ko,, A. Von Gottberg,, S. Mohapatra,, J. M. Casellas,, H. Goossens,, L. Mulazimoglu,, G. Trenholme,, K. P. Klugman,, R. A. Bonomo,, L. B. Rice,, M. M. Wagener,, J. G. McCormack,, and V. L. Yu. 2004- International prospective study of Klebsiella pneumoniae bacteremia: implications of extended-spectrum beta-lactamase production in nosocomial infection. Ann. Intern. Med. 140:2632.
207. Paton, R.,, R. S. Miles,, J. Hood,, and S. G. B. Amyes. 1993. ARI-1: beta-lactamase-mediated imipenem resistance in Acinetobacter baumannii. Int. J. Antimicrob. Agent. 2:8188.
208. Paulsen, I. T.,, L. Banerjei,, G. S. Myers,, K. E. Nelson,, R. Seshadri,, T. D. Read,, D. E. Fouts,, J. A. Eisen,, S. R. Gill,, J. F. Heidelberg,, H. Tettelin,, R. J. Dodson,, L. Umayam,, L. Brinkac,, M. Beanan,, S. Daugherty,, R. T. DeBoy,, S. Durkin,, J. Kolonay,, R. Madupu,, W. Nelson,, J. Vamathevan,, B. Tran,, J. Upton,, T. Hansen,, J. Shetty,, H. Khouri,, T. Utterback,, D. Radune,, K. A. Ketchum,, B. A. Dougherty,, and C. M. Fraser. 2003. Role of mobile DNA in the evolution of vancomycin-resistant Enterococcus faecalis. Scienc. 299:20712074.
209. Perichon, B.,, and P. Courvalin. 2009. VanA-type vancomycin-resistant Staphylococcus aureus. Antimicrob. Agents Chemother. 53:4580587.
210. Perl, T. M.,, J. J. Cullen,, R. P. Wenzel,, M. B. Zimmerman,, M. A. Pfaller,, D. Sheppard,, J. Twombley,, P. P. French,, and L. A. Herwaldt. 2002. Intranasal mupirocin to prevent postoperative Staphylococcus aureus infections. N. Engl. J. Me. 346:18711877.
211. Philippon, A.,, R. Labia,, and G. A. Jacoby. 1989. Extended-spectrum β-lactamase. Antimicrob. Agents Chemother. 33: 11311136.
212. Piddock, L. J. V. 1999. Mechanisms of fluoroquinolone resistance: an update 1994-1998. Drags 58:1118.
213. Pinho, M. G.,, H. de Lencastre,, and A. Tomasz. 2001. An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococc. Proc. Natl. Acad. Sci. US. 98:1088610891.
214. Podglajen, I.,, J. Breuil,, A. Rohaut,, C. Monsempes,, and E. Collatz. 2001. Multiple mobile promoter regions for the rare carbapenem resistance gene of Bacteroides fragilis. J. Bacteriol. 183:35313535.
215. Poirel, L.,, L. Collet,, and P. Nordmann. 2000. Carbapenem-hydrolyzing metallo-beta-lactamase from a nosocomial isolate of Pseudomonas aeruginosa in Franc. Emerg. Infect. Dis. 6:8485.
216. Poirel, L.,, P. Gerome,, C. De Champs,, J. Stephanazzi,, T. Naas,, and P. Nordmann. 2002. Integron-located oxa-32 gene cassette encoding an extended-spectrum variant of OXA-2 β-lactamase from Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 46:566569.
217. Poirel, L.,, D. Girlich,, T. Naas,, and P. Nordmann. 2001. OXA-28, an extended-spectrum variant of OXA-10 β-lactamase from Pseudomonas aeruginosa and its plasmid- and integron-located gen. Antimicrob. Agents Chemother. 45:44753.
218. Poirel, L.,, H. Mammeri,, and P. Nordmann. 2004. TEM-121, a novel complex mutant of TEM-type β-lactamase from Enterobacter aerogenes. Antimicrob. Agents Chemother. 48:4528531.
219. Poirel, L.,, T. Naas,, M. Guibert,, E. B. Chaibi,, R. Labia,, and P. Nordmann. 1999. Molecular and biochemical characterization of VEB-1, a novel class A extended-spectrum β-lactamase encoded by an Escherichia coli integron gen. Antimicrob. Agents Chemother. 43:573581.
220. Poirel, L.,, T. Naas,, and P. Nordmann. 2010. Diversity, epidemiology, and genetics of class D β-lactamase. Antimicrob. Agents Chemother. 54:2438.
221. Poirel, L.,, G. F. Weldhagen,, T. Naas,, C. De Champs,, M. G. Dove,, and P. Nordmann. 2001. GES-2, a class A β-lactamase from Pseudomonas aeruginosa with increased hydrolysis of imipene. Antimicrob. Agents Chemother. 45:25982603.
222. Poole, K.,, K. Krebes,, C. McNally,, and S. Neshat. 1993. Multiple antibiotic resistance in Pseudomonas aeruginosa: evidence for involvement of an efflux opero. J. Bacteriol. 175:73637372.
223. Prinarakis, E. E.,, V. Miriagou,, E. Tzelepi,, M. Gazouli,, and L. S. Tzouvelekis. 1997. Emergence of an inhibitor-resistant beta-lactamase (SHV-10) derived from an SHV-5 varian. Antimicrob. Agents Chemother. 41:838840.
224. Prystowsky, J.,, F. Siddiqui,, J. Chosay,, D. L. Shinabarger,, J. Millichap,, L. R. Peterson,, and G. A. Noskin. 2001. Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomycin-resistant enterococc. Antimicrob. Agents Chemother. 45:21542156.
225. Qiu, W.,, R. Shi,, M. L. Lu,, M. Zhou,, P. H. Roy,, J. Lapointe,, and S. X. Lin. 2004. Crystal structure of chloram-phenicol acetyltransferase B2 encoded by the multiresistance transposon Tn2424. Protein. 57:858861.
226. Queenan, A. M.,, and K. Bush. 2007. Carbapenemases: the versatile P-lactamase. Clin. Microbiol. Rev. 20:440458.
227. Race, P. R.,, A. L. Lovering,, R. M. Green,, A. Ossor,, S. A. White,, P. F. Searle,, C. J. Wrighton,, and E. I. Hyde. 2005. Structural and mechanistic studies of Escherichia coli nitroreductase with the antibiotic nitrofurazone. Reversed binding orientations in different redox states of the enzym. J. Biol. Chem. 280:1325613264.
228. Raquet, X.,, J. Lamotte-Brasseur,, E. Fonze,, S. Goussard,, P. Courvalin,, and J. M. Frere. 1994- TEM beta-lactamase mutants hydrolysing third-generation cephalosporins. A kinetic and molecular modelling analysi. J. Mol. Bio. 244:625639.
229. Rasmussen, B. A.,, K. Bush,, D. Keeney,, Y. Yang,, R. Hare,, C. O'Gara,, and A. A. Medeiros. 1996. Characterization of IMI-1 β-lactamase, a class A carbapenem-hydrolyzing enzyme from Enterobacter cloacae. Antimicrob. Agents Chemothe. 40:20802086.
230. Rather, P. N. 1998. Origins of aminoglycoside modifying enzyme. Drug Resist. Update. 1:285291.
231. Rather, P. N.,, E. Orosz,, K. J. Shaw,, R. Hare,, and G. Miller. 1993. Characterization and transcriptional regulation of the 2'-N-acetyltransferase gene from Providencia stuartii. J. Bacteriol. 175:64926498.
232. Rice, L. B. 2000. Bacterial monopolists: the bundling and dissemination of antimicrobial resistance genes in gram-positive bacteri. Clin. Infect. Dis. 31:762769.
233. Rice, L. B. 1998. Tn916 family conjugative transposons and dissemination of antimicrobial resistance determinants. Antimicrob. Agents Chemother. 42:18711877.
234. Rice, L. B.,, S. Bellais,, L. L. Carias,, R. Hutton-Thomas,, R. A. Bonomo,, P. Caspers,, M. G. Page,, and L. Gutmann. 2004. Impact of specific pbp5 mutations on expression of β-lactam resistance in Enterococcus faecium. Antimicrob. Agents Chemother. 48:30283032.