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Oxazolidinone Antibacterial Agents

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Antibiotic Discovery and Development

Abstract

The “golden age” of antibacterial agent discovery commenced with the identification of the sulfa drugs in the mid 1930s and concluded with the emergence of the quinolones in the early 1960s (Fig. 8.1). It is interesting to note that the vast majority of these early antibiotics were derived from natural products. Somewhat surprisingly, at least through the beginning of the year 2000, all subsequent marketed antibiotics have been largely semi-synthetic or synthetic variations of pre-existing antibacterial scaffolds.

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References

  1. Armstrong GL, Conn LA, Pinner RW (1999) Trends in infectious disease mortality in the United States during the 20th century. JAMA 281:61–66

    Article  PubMed  CAS  Google Scholar 

  2. Talbot GH, Bradley J, Jr Edwards JE et al (2006) Bad bugs need drugs: an update on the development pipeline from the antimicrobial availability task force of the infectious diseases society of America. Clin Infect Dis 42:657–668

    Article  PubMed  Google Scholar 

  3. Cardo D, Horan T, Andrus M et al (2004) National nosocomial infections surveillance (NNIS) system report. Am J Infect Control 32:470–485

    Article  Google Scholar 

  4. Klevens RM, Morrison M, Nadle AJ et al (2007) Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA 298:1763–1771

    Article  PubMed  CAS  Google Scholar 

  5. Nordmann P, Naas T, Fortineau N et al (2007) Superbugs in the coming new decade; multidrug resistance and prospects for treatment of Staphylococcus aureus, Entercoccus spp. and Pseudomonas aeruginosa in 2010. Curr Opin Microbiol 10:436

    Article  PubMed  CAS  Google Scholar 

  6. EnochD A, Birkett CL, Ludlam HA (2007) Non-fermentative Gram-negative bacteria. Int J Antimicrob Agents 29(Suppl 3):S33–S41

    Article  Google Scholar 

  7. Ferrara AM (2006) Potentially multidrug-resistant non-fermentative gram-negative pathogens causing nosocomial pneumonia. Int J Antimicrob Agents 27:183–195

    Article  PubMed  CAS  Google Scholar 

  8. Rice LB (2006) Challenges in identifying new antimicrobial agents effective for treating infections with Acinetobacter baumannii and Pseudomonas aeruginosa. Clin Infect Dis 43(Suppl 2):S100–S105

    Article  PubMed  CAS  Google Scholar 

  9. Silver LL, Bostian KA (1993) Discovery and development of new antibiotics: the problem of antibiotic resistance. Antimicrob Agents Chemother 37:377–383

    PubMed  CAS  Google Scholar 

  10. Barbachyn MR (2008) Recent advances in the discovery of hybrid antibacterial agents. In: Macor JE (ed) Annual reports in medicinal chemistry, vol 43. Elsevier, Netherlands, pp 281–290

    Google Scholar 

  11. Fugitt RB, Luckenbaugh RW (1978) 5-Halomethyl-3-phenyl-2-oxazolidinones. U.S. Patent 4,128,654

    Google Scholar 

  12. Fugitt RB, Luckenbaugh RW (1982) 3-(p-Alkylsulfonylphenyl)oxazolidinone derivatives as antibacterial agents. U.S. Patent 4,340,606

    Google Scholar 

  13. Gregory WA (1984) p-Oxooxazolidinylbenzene compounds as antibacterial agents. U.S. Patent 4,461,773

    Google Scholar 

  14. Gregory WA (1984) Aminomethyl oxooxazolidinyl benzene derivatives useful as antibacterial agents. Eur Pat Appl 127902

    Google Scholar 

  15. Slee AM, Wuonola MA, McRipley RJ, et al (1987) Oxazolidinones, a new class of synthetic antibacterials; in vitro and in vivo activities of DuP 105 and DuP 721. Abstracts of Papers 27th Interscience Conference on Antimicrobial Agents and Chemotherapy (New York, NY), Abstract No. 244. Slee A M, Wuonola MA, McRipley RJ, et al (1987) Oxazolidinones, a new class of synthetic antibacterial agents: in vitro and in vivo activities of DuP 105 and DuP 721. Antimicrob Agents Chemother 31: 1791–1797

    Google Scholar 

  16. Gregory WA, Brittelli DR, Wang CL et al (1989) Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 1. The B group. J Med Chem 32:1673–1681

    Article  PubMed  CAS  Google Scholar 

  17. Gregory WA, Brittelli DR, Wang CLJ et al (1990) Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxooxazolidines. 2. The “A” group. J Med Chem 33:2569–2578

    Article  PubMed  CAS  Google Scholar 

  18. Park CH, Brittelli DR, Wang CL et al (1992) Antibacterials. Synthesis and structure-activity studies of 3-aryl-2-oxazolidinones. 4. Multiply-substituted aryl derivatives. J Med Chem 35:1156–1165

    Article  PubMed  CAS  Google Scholar 

  19. Ranger L (2004) In: Batts DH, Kollef MH, Lipsky BA, Nicolau DP, Weigelt JA (eds) Creation of a Novel Class: The Oxazolidinone Antibiotics. Innova Institute for Medical Education, Tampa

    Google Scholar 

  20. Brickner SJ (1996) Oxazolidinone antibacterial agents. Curr Pharm Des 2:175–194

    CAS  Google Scholar 

  21. Gleave DM, Brickner SJ, Manninen PR et al (1998) Synthesis and antibacterial activity of [6,5,5] and [6,6,5] tricyclic fused oxazolidinones. Bioorg Med Chem Lett 8:1231–1236

    Article  PubMed  CAS  Google Scholar 

  22. Brickner SJ, Barbachyn MR, Hutchnson DK et al (2008) 2007 American Chemical Society Team innovation award address. Linezolid (Zyvox), the first member of a completely new class of antibacterial agents for treatment of serious gram-positive infections. J Med Chem 51:1981–1990

    Article  PubMed  CAS  Google Scholar 

  23. Brickner SJ (1992) 5′-Indolinyl-5.beta.-amidomethyloxazolidin-2-ones. U.S. Patent 5,164,510

    Google Scholar 

  24. Wang CLJ, Gregory WA, Wuonola MA (1989) Chiral synthesis of DuP 721, a new antibacterial agent. Tetrahedron 45:1323–1326

    Article  CAS  Google Scholar 

  25. Manninen PR, Little HA, Brickner SJ (1996) Investigation into the metal ion dependency of the regiospecific alkylation/cyclization reaction producing 5-(R)-hydroxymethyl-3-aryl-oxazolidinones. Book of abstracts, 212th ACS national meeting, Orlando, FL, August 25–29, Abstract No. ORGN-389

    Google Scholar 

  26. Manninen PR, Brickner SJ (2005) Preparation of N-aryl-5R-hydroxymethyl-2-oxazolidinones from N-aryl carbamates: N-phenyl-(5R)-hydroxymethyl-2-oxazolidinone. Org Syn 8(1): 112–120

    Google Scholar 

  27. Barbachyn MR, Toops DS, Ulanowicz DA et al (1996) Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents. 1. Identification of leads and importance of the tropone substitution pattern. Bioorg Med Chem Lett 6:1003–1008

    Article  Google Scholar 

  28. Barbachyn MR, Toops DS, Grega KC et al (1996) Synthesis and antibacterial activity of new tropone-substituted phenyloxazolidinone antibacterial agents. 2. Modification of the phenyl ring – the potentiating effect of fluorine substitution on in vivo activity. Bioorg Med Chem Lett 6:1009–1014

    Article  CAS  Google Scholar 

  29. Hutchinson DK, Barbachyn MR, Brickner SJ, et al (1995) Piperazinyl oxazolidinones: structure activity relationships of a new class of oxazolidinone antibacterial agents. 35th Interscience conference on antimicrobial agents and chemotherapy, San Francisco, CA, 17–20 Sep, F-207

    Google Scholar 

  30. Hutchinson DK, Barbachyn MR, Brickner SJ, et al (1996) Structure-activity relationships of piperazinylphenyl oxazolidinone antibacterial agents and related developments. 212th ACS national meeting, Orlando, FL, 25–29 Aug, MEDI-192

    Google Scholar 

  31. BarbachynM R, Ford CW (2003) Oxazolidinone structure-activity relationships leading to linezolid. Angew Chem Int Ed 42:2010–2023

    Article  CAS  Google Scholar 

  32. Brickner SJ, Hutchinson DK, Barbachyn MR et al (1996) Synthesis and antibacterial activity of U-100592 and U-100766, two oxazolidinone antibacterial agents for the potential treatment of multidrug-resistant gram-positive bacterial infections. J Med Chem 39:673–679

    Article  PubMed  CAS  Google Scholar 

  33. Barbachyn MR, Brickner SJ, Cleek GJ et al (1997) Design and synthesis of novel oxazolidinones active against multidrug-resistant bacteria. In: O’Hanlon PJ (ed) Anti-infectives: recent advances in chemistry and structure-activity relationships: PH Bentley. The Royal Society of Chemistry, Cambridge, pp 15–26

    Google Scholar 

  34. Barbachyn MR, Brickner SJ, Gadwood RC et al (1998) Design, synthesis, and evaluation of novel oxazolidinone antibacterial agents active against multidrug-resistant bacteria. In: Rosen BP, Mobashery S (eds) Resolving the antibiotic paradox, vol 456. Kluwer/Plenum, New York, Chapter 12

    Chapter  Google Scholar 

  35. Barbachyn MR, Hutchinson DK, Brickner SJ et al (1996) Identification of a novel oxazolidinone (U-100480) with potent anti-mycobacterial activity. J Med Chem 39:680–685

    Article  PubMed  CAS  Google Scholar 

  36. Slatter JG, Adams LA, Bush EC et al (2002) Pharmacokinetics, toxicokinetics, distribution, metabolism and excretion of linezolid in mouse, rat and dog. Xenobiotica 32:907–924

    Article  PubMed  CAS  Google Scholar 

  37. Zurenko GE, Ford CW, Hutchinson DK et al (1997) Oxazolidinone antibacterial agents; development of the clinical candidates eperezolid and linezolid. Exp Opin Invest Drugs 6:151–158

    Article  CAS  Google Scholar 

  38. Stalker DJ, Jungbluth GL, Hopkins NK, Batts DH (2003) Pharmacokinetics and tolerance of single- and multiple-dose oral or intravenous linezolid, an oxazolidinone antibiotic, in healthy volunteers. J Antimicrob Chemother 51:1239–1246

    Article  PubMed  CAS  Google Scholar 

  39. Stalker DJ, Jungbluth GL (2003) Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmacokinet 42:1129–1140

    Article  PubMed  CAS  Google Scholar 

  40. Slatter JG, Stalker DJ et al (2001) Pharmacokinetics, metabolism and excretion of linezolid following an oral dose of [14  C]linezolid to healthy human subjects. Drug Metab Dispos 29:1136–1145

    PubMed  CAS  Google Scholar 

  41. Wynalda MA, Hauer MJ, Wienkers LC (2000) Oxidation of the novel oxazolidinone antibiotic linezolid in human liver microsomes. Drug Metab Disp: Biol Fate Chem 28:1014–1017

    CAS  Google Scholar 

  42. Welshman IR, Sisson TA, Jungbluth GL et al (2001) Linezolid absolute bioavailability and the effect of food on oral bioavailability. Biopharm Drug Disposition 22:91–97

    Article  CAS  Google Scholar 

  43. Conte JE Jr, Golden JA, Kipps J et al (2002) Intrapulmonary pharmacokinetics of linezolid. Antimicrob Agents Chemother 46:1475–1480

    Article  PubMed  CAS  Google Scholar 

  44. San Pedro GS, Cammarata SK, Oliphant TH et al (2002) Linezolid versus ceftriaxone/cefpodoxime in patients hospitalized for the treatment of Streptococcus pneumoniae pneumonia. Scand J Infect Dis 34:720–728

    Article  PubMed  Google Scholar 

  45. Rubinstein E, Cammarata SK, Oliphant TH et al (2001) And the linezolid nosocomial pneumonia study group. Linezolid (PNU-100766) versus vancomycin in the treatment of hospitalized patients with nosocomial pneumonia: a randomized, double blind, multi-center study. Clin Inf Dis 32:402–412

    Article  CAS  Google Scholar 

  46. Stevens DL, Smith LG, Bruss JB et al (2000) Randomized comparison of linezolid (PNU-100766) versus oxacillin-dicloxacillin for treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 44:3408–3413

    Article  PubMed  CAS  Google Scholar 

  47. Ford CW, Zurenko GE, Barbachyn MR (2001) The discovery of linezolid, the first oxazolidinone antibacterial agent. Curr Drug Targets Infect Disord 1:181–199

    Article  PubMed  CAS  Google Scholar 

  48. French G (2003) Safety and tolerability of linezolid. J Antimicrob Chemother 51(Suppl S2): ii45–ii53

    PubMed  CAS  Google Scholar 

  49. Rubinstein E, Isturiz R, Standiford HC et al (2003) Worldwide assessment of linezolid’s clinical safety and tolerability: comparator-controlled phase III studies. Antimicrob Agents Chemother 47:1824–1831

    Article  PubMed  CAS  Google Scholar 

  50. Zyvox™ (linezolid) package insert, Phamacia, Upjohn, revised June 2010 http://www.pfizer.com/products/rx/rx_product_zyvox.jsp

  51. Humphrey SJ, Curry JT, Turman CN et al (2001) Cardiovascular sympathomimetic amine interactions in rats treated with monoamine oxidase inhibitors and the novel oxazolidinone antibiotic linezolid. J CardiovascPharmacol 37:548–563

    CAS  Google Scholar 

  52. Bergeron L, Boulé M, Perreault S (2005) Serotonin toxicity associated with concomitant use of linezolid. Ann Pharmacotherapy 39:956–961

    Article  Google Scholar 

  53. Gillman PK (2003) Linezolid and serotonin toxicity. Clin Infect Dis 37:1274–1275

    Article  PubMed  Google Scholar 

  54. Wigen CL, Goetz MB (2002) Serotonin syndrome and linezolid. Clin Infect Dis 34: 1651–1652

    Article  PubMed  Google Scholar 

  55. Apodaca AA, Rakita RM (2003) Linezolid-induced lactic acidosis. N Engl J Med 348: 86–87

    Article  PubMed  Google Scholar 

  56. Palenzuela L, Hahn NM, Nelson RP Jr et al (2005) Does linezolid cause lactic acidosis by inhibiting mitochondrial protein synthesis? Clin Infect Dis 40:e113–e116

    Article  PubMed  Google Scholar 

  57. Bressler AM, Zimmer SM, Gilmore JL et al (2004) Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis 4:528–531

    Article  PubMed  Google Scholar 

  58. Zivkovic SA, Lacomis D (2005) Severe sensory neuropathy associated with long-term linezolid use. Neurology 64:926–927

    Article  PubMed  Google Scholar 

  59. Lee E, Burger S, Shah J et al (2003) Linezolid-associated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis 37:1389–1391

    Article  PubMed  Google Scholar 

  60. Senneville E, Legout L, Valette M et al (2006) Effectiveness and tolerability of prolonged linezolid treatment for chronic osteomyelitis: a retrospective study. Clin Ther 28:1155–1163

    Article  PubMed  CAS  Google Scholar 

  61. Beekmann SE, Gilbert DN, Polgreen PM (2009) Toxicity of extended courses of linezolid: results of an infectious diseases society of America emerging infections network survey. Diagn Microbiol Infect Dis 62:407–410

    Article  CAS  Google Scholar 

  62. McKee EE, Ferguson M, Bentley AT et al (2006) Inhibition of mammalian mitochondrial protein synthesis by oxazolidinones. Antimicrob Agents Chemother 50:2042–2049

    Article  PubMed  CAS  Google Scholar 

  63. Garrabou G, Soriano A et al (2007) Reversible inhibition of mitochondrial protein synthesis during linezolid-related hyperlactatemia. Antimicrob Agents Chemother 51:962–967

    Article  PubMed  CAS  Google Scholar 

  64. Denis A, Vilette T (1994) 5-Aryl-β, γ butenolide, a new class of antibacterial derived from the N-aryl oxazolidinone DuP 721. Bioorg Med Chem Lett 4:1925–1930

    Article  Google Scholar 

  65. Borthwick AD, Biggadike K, Rocherolle V et al (1996) 5-(Acetamidomethyl)-3-aryldihydrofuran-2-ones and 5-(acetamidomethyl)-3-aryltetrahydrofuran-2-ones. Two new classes of antibacterial agents. Med Chem Res 6:22–27

    CAS  Google Scholar 

  66. Hester JB, Brickner SJ, Barbachyn M R, et al (1998) S. 5-Amidomethyl α,β-saturated and unsaturated 3-aryl butyrolactone antibacterial agents. U.S. Patent 5,708,169

    Google Scholar 

  67. Barbachyn MR, Cleek GJ et al (2003) Identification of phenylisoxazolines as novel and viable antibacterial agents active against Gram-positive bacteria. J Med Chem 46:284–302

    Article  PubMed  CAS  Google Scholar 

  68. Snyder LB, Meng Z (2004) Discovery of isoxazolinone antibacterial agents. Nitrogen as a replacement for the stereogenic center found in oxazolidinone antibacterials. Bioorg Med Chem Lett 14:4735–4739

    Article  PubMed  CAS  Google Scholar 

  69. Quesnelle CA, Gill P et al (2005) Biaryl isoxazolinone antibacterial agents. Bioorg Med Chem Lett 15:2728–2733

    Article  PubMed  CAS  Google Scholar 

  70. Gravestock MB, Acton DG et al (2003) New classes of antibacterial oxazolidinones with C-5, methylene O-linked heterocyclic side chains. Bioorg Med Chem Lett 13:4179–4186

    Article  PubMed  CAS  Google Scholar 

  71. Reck F, Zhou F et al (2005) Identifcation of 4-substituted 1,2,3-triazoles as novel oxazolidinone antibacterial agents with reduced activity against monoamine oxidase A. J Med Chem 48:499–506

    Article  PubMed  CAS  Google Scholar 

  72. Reck F, Zhou F et al (2007) Novel substituted (pyridin-3-yl)phenyloxazolidinones: antibacterial agents with reduced activity against monoamie oxidase A and increased solubility. J Med Chem 50:4868–4881

    Article  PubMed  CAS  Google Scholar 

  73. Anderegg TR, Biedenbach DJ, Jones RN (2002) In vitro evaluation of AZD2563, a new oxazolidinone, tested against β-hemolytic and viridians group streptococci. J Antimicrob Chemother 49:1019–1021

    Article  PubMed  CAS  Google Scholar 

  74. Fluit AC, Schmitz FJ et al (2002) In vitro activity of AZD2563, a novel oxazolidinone, against European Gram-positive cocci. J Antimicrob Chemother 50:271–276

    Article  PubMed  CAS  Google Scholar 

  75. Baum SE, Crawford SA et al (2002) Comparative activitiesof the oxazolidinone AZD2563 and linezolid against selected recent North American isolates of Streptococcus pneumoniae. Antimicrob Agents Chemother 46:3094–3095

    Article  PubMed  CAS  Google Scholar 

  76. Howe RA, Wootton M et al (2003) Activity of AZD2563, a novel oxazolidinone, against Staphylococcus aureus strains with reduced susceptibility to vancomycin and linezolid. Antimicrob Agents Chemother 47:3651–3652

    Article  PubMed  CAS  Google Scholar 

  77. Wookey A, Turner PJ et al (2004) AZD2563, a novel oxazolidinone: definition of antibacterial spectrum, assessment of bactericidal potential and the impact of miscellaneous factors on activity in vitro. Clin Microbiol Infect 10:247–254

    Article  PubMed  CAS  Google Scholar 

  78. Poel TJ, Thomas RC et al (2007) Antibacterial oxazolidinones possessing a novel C-5 side chain. (5R)-trans-3-[3-fluoro-4-(1-oxotetrahydrothiopyran-4-yl)phenyl]-2-oxooxazolidinone-5-carboxylic acid amide (PF-00422602), a new lead compound. J Med Chem 50: 5886–5889

    Article  PubMed  CAS  Google Scholar 

  79. Penzien JB, Huband MD, et al (2009) In vitro and in vivo activity of PF-00708093 and PF-02341752: new oxazolidinone antibacterials versus recent bacterial clinical isolates. Book of abstracts, 49th Interscience conference on antimicrobial agents and chemotherapy, San Francisco, CA, F1-1511

    Google Scholar 

  80. Im W, Choi S, Rhee J (2007) Structure-activity relationship of substituted pyridyl phenyl oxazolidinone derivatives, including TR-700 (DA–7157). Book of abstracts, 47th Interscience conference on antimicrobial agents and chemotherapy, Chicago, IL, F1–1686

    Google Scholar 

  81. Gordeev MF, Hackbarth C et al (2003) Novel oxazolidinone-quinolone hybrid antibacterials. Bioorg Med Chem Lett 13:4213–4216

    Article  PubMed  CAS  Google Scholar 

  82. Hubschwerlen C, Specklin JL et al (2003) Structure-activity relationship in the oxazolidinone-quinolone hybrid series: influence of the central spacer on the antibacterial activity and the mode of action. Bioorg Med Chem Lett 13:4229–4233

    Article  PubMed  CAS  Google Scholar 

  83. Hubschwerlen C, Specklin JL et al (2003) Design, synthesis and biological evaluation of oxazolidinone-quinolone hybrids. Bioorg Med Chem 11:2313–2319

    Article  PubMed  CAS  Google Scholar 

  84. Gray CP, Cappi MW (2005) Efficacy Studies of MCB 3837, a dual-action antibiotic, in experimental infections in mice. Book of abstracts, 45th Interscience conference on antimicrobial agents and chemotherapy, Washington, DC, F-513

    Google Scholar 

  85. Dalhoff A (2007) Quinolone-Oxazolidine Hybrids.0 47th Interscience conference on antimicrobial agents and chemotherapy, Chicago, 48(F) Symposium, F-638

    Google Scholar 

  86. Lawrence L, Danese P et al (2008) In vitro activities of the Rx-01 oxazolidinones against hospital and community pathogens. Antimicrob Agents Chemother 52:1653–1662

    Article  PubMed  CAS  Google Scholar 

  87. Skripkin E, McConnell ES et al (2008) Rx-01, a new family of oxazolidinones that overcome ribosome-based linezolid resistance. Antimicrob Agents Chemother 52:3550–3557

    Article  PubMed  CAS  Google Scholar 

  88. Cynamon MH, Klemens SP et al (1999) Activities of several novel oxazolidinones against Mycobacterium tuberculosis in a murine model. Antimicrob Agents Chemother 43:1189–1191

    PubMed  CAS  Google Scholar 

  89. Williams KN, Stover CK et al (2009) Promising antituberculosis activity of the oxazolidinone PNU-100480 relative to that of linezolid in a murine model. Antimicrob Agents Chemother 53:1314–1319

    Article  PubMed  CAS  Google Scholar 

  90. Williams KN, Brickner SJ et al (2009) Addition of PNU-100480 to first-line drugs shortens the time needed to cure murine tuberculosis. Am J Respir Crit Care Med 180:371–376

    Article  PubMed  CAS  Google Scholar 

  91. Wallis RS, Jakubiec WM et al (2010) Pharmacokinetics and whole-blood bactericidal activity against Mycobacterium tuberculosis of single doses of PNU-100480 in healthy volunteers. J Infect Dis 202:745–751

    Article  PubMed  CAS  Google Scholar 

  92. Huband MD, Stover CK (2009) In vitro activity of PNU-100480, PNU-101603, and PNU-101244: novel oxazolidinone antibacterials versus Mycobacterium tuberculosis. Book of abstracts, 49th Interscience conference on antimicrobial agents and chemotherapy, San Francisco, CA, F1-1512

    Google Scholar 

  93. Wallis RS, et al (2010) Safety, tolerability, PK and whole blood bactericidal activity (WBA) against M. tuberculosis of multiple ascending doses of PNU-100480. Book of Abstracts, 50th Interscience conference on antimicrobial agents and chemotherapy, San Francisco, CA, A1-030a

    Google Scholar 

  94. Nagiec EE, Swaney SM et al (2005) Oxazolidinones inhibit cellular proliferation via inhibition of mammalian mitochondrial protein synthesis. Antimicrob Agents Chemother 49:3896–3902

    Article  PubMed  CAS  Google Scholar 

  95. McKee EE, Ferguson M et al (2006) Inhibition of mammalian mitochondrial protein synthesis by oxaolidinones. Antimicrob Agents Chemother 50:2042–2049

    Article  PubMed  CAS  Google Scholar 

  96. Koul A, Arnoult E et al (2011) The challenge of new drug discovery for tuberculosis. Nature 469:483–490

    Article  PubMed  CAS  Google Scholar 

  97. Ma Z, Lienhardt C et al (2010) Global tuberculosis drug development pipeline: the need and the reality. Lancet 375: 2100–2109. www.clinicaltrials.gov

    Google Scholar 

  98. Kehrenberg C, Schwarz S et al (2005) A new mechanism for chloramphenicol, florfenicol and clindamycin resistance: methylation of 23S ribosomal RNA at A2503. Mol Microbiol 57:1064–1073

    Article  PubMed  CAS  Google Scholar 

  99. Giessing AM, Jensen SS et al (2009) Identification of 8-methyladenosine as the modification catalyzed by the radical SAM methyltransferase Cfr that confers antibiotic resistance in bacteria. RNA 15:327–336

    Article  PubMed  CAS  Google Scholar 

  100. Locke JB, Finn J et al (2010) Structure-activity relationships of diverse oxazolidinones for linezolid-resistant Staphylococcus aureus strains possessing the cfr methyltransferase gene or ribosomal mutations. Antimicrob Agents Chemother 54:5337–5343

    Article  PubMed  CAS  Google Scholar 

  101. Shaw KJ, Poppe S et al (2008) In vitro activity of TR-700, the antibacterial moiety of the prodrug TR-701, against linezolid-resistant strains. Antimicrob Agents Chemother 52: 4442–4447

    Article  PubMed  CAS  Google Scholar 

  102. Schaadt R, Sweeney D et al (2009) In vitro activity of TR-700, the active ingredient of the antibacterial prodrug TR-701, a novel oxazolidinone antibacterial agent. Antimicrob Agents Chemother 53:3236–3239

    Article  PubMed  CAS  Google Scholar 

  103. Long KS, Poehlsgaard J et al (2006) The cfr rRNA methyltransferase confers resistance to phenicols, lincosamides, oxazolidinones, pleuromutilins, and streptogramin A antibiotics. Antimicrob Agents Chemother 50:2500–2505

    Article  PubMed  CAS  Google Scholar 

  104. Locke JB, Morales G et al (2010) Elevated linezolid resitance in clinical cfr-positive Staphylococcus aureus isolates is associated with co-occurring mutations in ribosomal protein L3. Antimicrob Agents Chemother 54:5352–5355

    Article  PubMed  CAS  Google Scholar 

  105. Leach KL, Swaney SM et al (2007) The site of action of oxazolidinone antibiotics in living bacteria and in human mitochondria. Mol Cell 26:393–402

    Article  PubMed  CAS  Google Scholar 

  106. Colca JR, McDonald WG et al (2003) Crosslinking in the living cell locates the site of action of oxazolidinone antibiotics. J Biol Chem 278:21972–21979

    Article  PubMed  CAS  Google Scholar 

  107. Ippolito JA, Kanyo ZF et al (2008) Crystal structure of the oxazolidinone antibiotic linezolid bound to the 50 S ribosomal subunit. J Med Chem 51:3353–3356

    Article  PubMed  CAS  Google Scholar 

  108. Wilson DN, Schluenzen F (2008) The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and affect tRNA positioning. PNAS 105:13339–13344

    Article  PubMed  CAS  Google Scholar 

  109. Zurenko G E, Todd WM, et al (1999) Development of linezolid-resistant Enterococcus faecium in two compassionate use program patients treated with linezolid. Book of abstracts, 39th Interscience conference on antimicrobial agents and chemotherapy, San Francisco, CA, C-848

    Google Scholar 

  110. Shinabarger DL (1999) Mechanism of action of the oxazolidinone antibacterial agents. ExpOpin Invest Drugs 8:1195–1202

    Article  CAS  Google Scholar 

  111. Prystowsky J, Siddiqui F et al (2001) Resistance to linezolid: characterization of mutations in rRNA and comparison of their occurrences in vancomysin-resistant enterococci. Antimicrob Agents Chemother 45:2154–2156

    Article  PubMed  CAS  Google Scholar 

  112. Mutnick AH, Enne V, Jones RN (2003) Linezolid resistance since 2001: SENTRY antimicrobial surveillance program. Ann Pharmacother 37:769–774, and references cited therein

    Article  PubMed  CAS  Google Scholar 

  113. Long KS, Munck C et al (2010) Mutations in 23 S rRNA at the peptidyl transferase center and their relationship to linezolid binding and cross-resistance. Antimicrob Agents Chemother 54:4705–4713

    Article  PubMed  CAS  Google Scholar 

  114. Wolter N, Smith AM et al (2005) Novel mechanism of resistance to oxazolidinones, macrolides, and chloramphenicol in ribosomal protein L4 of the pneumococcus. Antimicrob Agents Chemother 49:3554–3557

    Article  PubMed  CAS  Google Scholar 

  115. Locke JB, Hilgers M et al (2009) Mutations in ribosomal protein L3 are associated with oxazolidinone resistance in staphylococci of clinical origin. Antimicrob Agents Chemother 53:5275–5278

    Article  PubMed  CAS  Google Scholar 

  116. Jones RN, Ross JE et al (2008) United States resistance surveillance results for linezolid (LEADER program for 2007). Diagn Microbiol Infect Dis 62:416–426

    Article  PubMed  CAS  Google Scholar 

  117. Jones RN, Shigeru K et al (2009) ZAAPS international surveillance program (2007) for linezolid resistance: results from 5591 Gram-positive isolates in 23 countries. Diagn Microbiol Infect Dis 64:191–201

    Article  PubMed  CAS  Google Scholar 

  118. Zhanel GG, DeCorby M et al (2010) Prevalence of antimicrobial-resistant pathogens in Canadian hospitals: results of the Canadian ward surveillance study (CANWARD 2008). Antimicrob Agents Chemother 54:4684–4693

    Article  PubMed  CAS  Google Scholar 

  119. Simor AE, Louie L et al (2010) Antimicrobial susceptibilities of health care-associated and community-associated strains of methicillin-resistant Staphylococcus aureus from hospitalized patients in Canad, 1995 to 2008. Antimicrob Agents Chemother 54:2265–2268

    Article  PubMed  CAS  Google Scholar 

  120. Mendes RE, Moet GJ et al (2010) In vitro activity of telavancin against a contemporary worldwide collection of Staphylococcus aureus isolates. Antimicrob Agents Chemother 54:2704–2706

    Article  PubMed  CAS  Google Scholar 

  121. Saravolatz L, Pawlak J et al (2010) In vitro activity of Ceftaroline against community-associated methicillin-resistant, vancomycin-intermediate, vancomycin-resistant, and daptomycin-nonsusceptible Staphylococcus aureus isolates. Antimicrob Agents Chemother 54:3027–3030

    Article  PubMed  CAS  Google Scholar 

  122. Bonora MG, Maurizio S et al (2006) Emergence of linezolid resistance in the vancomycin-resistant Enterococcus faecium multilocus sequence typing C1 epidemic lineage. J Clin Microbiol 44:1153–1155

    Article  PubMed  CAS  Google Scholar 

  123. Dobbs TE, Mukesh P et al (2006) Nosocomial spread of Enterococcus faecium resistant to vancomycin and linezolid in a tertiary care medical center. J Clin Microbiol 44:3368–3370

    Article  PubMed  CAS  Google Scholar 

  124. Jacobs MR, Good CE et al (2010) Activity of Ceftaroline against recent emerging serotypes of Streptococcus pneumoniae in the United States. Antimicrob Agents Chemother 54:2716–2719

    Article  PubMed  CAS  Google Scholar 

  125. Farrell DJ, Morrissey I et al (2004) In vitro activities of telithromycin, linezolid, and quinupristin-dalfopristin against Streptococcus pneumoniae with macrolide resistance due to ribosomal mutations. Antimicrob Agents Chemother 48:3169–3171

    Article  PubMed  CAS  Google Scholar 

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  1. AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA, 02451, USA

    Michael R. Barbachyn

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Correspondence to Michael R. Barbachyn .

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  1. , Senior Principal Scientist, AstraZeneca Pharmaceuticals LP, Gatehouse Dr. 35, Waltham, 02451, Massachusetts, USA

    Thomas J. Dougherty

  2. Achillion Pharmaceuticals, Inc., George St. 300, New Haven, 06511, Connecticut, USA

    Michael J. Pucci

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Barbachyn, M.R. (2012). Oxazolidinone Antibacterial Agents. In: Dougherty, T., Pucci, M. (eds) Antibiotic Discovery and Development. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-1400-1_8

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