The Mechanisms of Resistance to β-Lactam Antibiotics

  • Dustin T. King
  • Solmaz Sobhanifar
  • Natalie C. J. StrynadkaEmail author
Reference work entry


Bacterial diseases have had an enormous impact on human health and continue to be a major focus in modern medicine. The most widespread class of human antibacterials is the β-lactams that target the transpeptidase enzymes, which are responsible for cross-linking the peptidoglycan cell wall. There are over 34 FDA-approved β-lactams which together constitute ~50 % of all antibiotic prescriptions worldwide (Tahlan K and Jensen SE, J Antibiot (Tokyo) 66:401–410, 2013). However, bacteria have gained resistance mechanisms to overcome all major classes of β-lactam antibiotics to date. In this chapter, we will address the major mechanisms of bacterial resistance to the β-lactams and highlight some of the recent advances in circumventing this resistance.


β-Lactams β-Lactamase Antibiotic resistance Efflux pump Penicillin-binding proteins 



We gratefully acknowledge the following funding agencies for supporting this work: Canadian Institute of Health Research (to SS, DTK, and NCJS), Howard Hughes Medical Institute (to NCJS), Canada Foundation for Innovation (to NCJS), British Columbia Knowledge Development Fund (to NCJS), and Michael Smith Foundation for Health Research (to SS).


  1. Abbate E et al (2011) Successful alternative treatment of extensively drug-resistant tuberculosis in Argentina with a combination of linezolid, moxifloxacin and thioridazine. J Antimicrob Chemother 67:473–477PubMedCrossRefGoogle Scholar
  2. Abraham EP, Chain E (1988) An enzyme from bacteria able to destroy penicillin. 1940. Rev Infect Dis 10:677–678PubMedCrossRefGoogle Scholar
  3. Amaral L, Molnar J (2012) Potential therapy of multidrug-resistant and extremely drug-resistant tuberculosis with thioridazine. In Vivo 26:231–236PubMedGoogle Scholar
  4. Amaral L, Martins M, Viveiros M, Molnar J, Kristiansen JE (2008) Promising therapy of XDR-TB/MDR-TB with thioridazine an inhibitor of bacterial efflux pumps. Curr Drug Targets 9:816–819PubMedCrossRefGoogle Scholar
  5. Amoroso A et al (2012) A peptidoglycan fragment triggers beta-lactam resistance in Bacillus licheniformis. PLoS Pathog 8:e1002571PubMedPubMedCentralCrossRefGoogle Scholar
  6. Andersen C et al (2002) Transition to the open state of the TolC periplasmic tunnel entrance. Proc Natl Acad Sci U S A 99:11103–11108PubMedPubMedCentralCrossRefGoogle Scholar
  7. Archer GL, Niemeyer DM, Thanassi JA, Pucci MJ (1994) Dissemination among staphylococci of DNA sequences associated with methicillin resistance. Antimicrob Agents Chemother 38:447–454PubMedPubMedCentralCrossRefGoogle Scholar
  8. Baba T et al (2009) Complete genome sequence of Macrococcus caseolyticus strain JCSCS5402, [corrected] reflecting the ancestral genome of the human-pathogenic staphylococci. J Bacteriol 191:1180–1190PubMedCrossRefGoogle Scholar
  9. Bavro VN et al (2008) Assembly and channel opening in a bacterial drug efflux machine. Mol Cell 30:114–121PubMedPubMedCentralCrossRefGoogle Scholar
  10. Bebrone C (2007) Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem Pharmacol 74:1686–1701PubMedCrossRefGoogle Scholar
  11. Bebrone C et al (2009) The structure of the dizinc subclass B2 metallo-beta-lactamase CphA reveals that the second inhibitory zinc ion binds in the histidine site. Antimicrob Agents Chemother 53:4464–4471PubMedPubMedCentralCrossRefGoogle Scholar
  12. Birck C et al (2004) X-ray crystal structure of the acylated beta-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction. J Am Chem Soc 126:13945–13947PubMedCrossRefGoogle Scholar
  13. Birnbaum J, Kahan FM, Kropp H, MacDonald JS (1985) Carbapenems, a new class of beta-lactam antibiotics. Discovery and development of imipenem/cilastatin. Am J Med 78:3–21PubMedCrossRefGoogle Scholar
  14. Bonfiglio G, Russo G, Nicoletti G (2002) Recent developments in carbapenems. Expert Opin Investig Drugs 11:529–544PubMedCrossRefGoogle Scholar
  15. Bowler LD, Zhang QY, Riou JY, Spratt BG (1994) Interspecies recombination between the penA genes of Neisseria meningitidis and commensal Neisseria species during the emergence of penicillin resistance in N. meningitidis: natural events and laboratory simulation. J Bacteriol 176:333–337PubMedPubMedCentralCrossRefGoogle Scholar
  16. Brannigan JA, Tirodimos IA, Zhang QY, Dowson CG, Spratt BG (1990) Insertion of an extra amino acid is the main cause of the low affinity of penicillin-binding protein 2 in penicillin-resistant strains of Neisseria gonorrhoeae. Mol Microbiol 4:913–919PubMedCrossRefGoogle Scholar
  17. Brown MH, Paulsen IT, Skurray RA (1999) The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 31:394–395PubMedCrossRefGoogle Scholar
  18. Bush K (2012) Evolution of beta-lactamases: past, present, and future. In: Dougherty TJ and Pucci MJ (ed) Antibiotic discovery and development. Springer, New York, pp 427–453Google Scholar
  19. Bush K (2013) Proliferation and significance of clinically relevant beta-lactamases. Ann N Y Acad Sci 1277:84–90PubMedCrossRefGoogle Scholar
  20. Bush K, Macielag MJ (2010) New beta-lactam antibiotics and beta-lactamase inhibitors. Expert Opin Ther Pat 20:1277–1293PubMedCrossRefGoogle Scholar
  21. Buynak JD (2013) beta-Lactamase inhibitors: a review of the patent literature (2010–2013). Expert Opin Ther Pat 23:1469–1481PubMedCrossRefGoogle Scholar
  22. Castanheira M, Williams G, Jones RN, Sader HS (2014) Activity of ceftaroline-avibactam tested against contemporary Enterobacteriaceae isolates carrying beta-lactamases prevalent in the United States. Microb Drug Resist 20:436–440PubMedCrossRefGoogle Scholar
  23. Cha J, Mobashery S (2007) Lysine N(zeta)-decarboxylation in the BlaR1 protein from Staphylococcus aureus at the root of its function as an antibiotic sensor. J Am Chem Soc 129:3834–3835PubMedCrossRefGoogle Scholar
  24. Cha J, Vakulenko SB, Mobashery S (2007) Characterization of the beta-lactam antibiotic sensor domain of the MecR1 signal sensor/transducer protein from methicillin-resistant Staphylococcus aureus. Biochemistry 46:7822–7831PubMedCrossRefGoogle Scholar
  25. Dabernat H et al (2002) Diversity of beta-lactam resistance-conferring amino acid substitutions in penicillin-binding protein 3 of Haemophilus influenzae. Antimicrob Agents Chemother 46:2208–2218PubMedPubMedCentralCrossRefGoogle Scholar
  26. de Seny D et al (2001) Metal ion binding and coordination geometry for wild type and mutants of metallo-beta -lactamase from Bacillus cereus 569/H/9 (BcII): a combined thermodynamic, kinetic, and spectroscopic approach. J Biol Chem 276:45065–45078PubMedCrossRefGoogle Scholar
  27. Delmas J et al (2010) Structural insights into substrate recognition and product expulsion in CTX-M enzymes. J Mol Biol 400:108–120PubMedCrossRefGoogle Scholar
  28. Deng X et al (2012) Expression of multidrug resistance efflux pump gene norA is iron responsive in Staphylococcus aureus. J Bacteriol 194:1753–1762PubMedPubMedCentralCrossRefGoogle Scholar
  29. Docquier JD et al (2009) Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol 16:540–547PubMedCrossRefGoogle Scholar
  30. Doumith M, Ellington MJ, Livermore DM, Woodford N (2009) Molecular mechanisms disrupting porin expression in ertapenem-resistant Klebsiella and Enterobacter spp. clinical isolates from the UK. J Antimicrob Chemother 63:659–667PubMedCrossRefGoogle Scholar
  31. Dowson CG, Coffey TJ, Spratt BG (1994) Origin and molecular epidemiology of penicillin-binding-protein-mediated resistance to beta-lactam antibiotics. Trends Microbiol 2:361–366PubMedCrossRefGoogle Scholar
  32. Duguid JP (1946) The sensitivity of bacteria to the action of penicillin. Edinb Med J 53:401–412PubMedGoogle Scholar
  33. Ellis-Grosse EJ, Babinchak T, Dartois N, Rose G, Loh E (2005) The efficacy and safety of tigecycline in the treatment of skin and skin-structure infections: results of 2 double-blind phase 3 comparison studies with vancomycin-aztreonam. Clin Infect Dis 41(Suppl 5):S341–S353PubMedCrossRefGoogle Scholar
  34. Farra A, Islam S, Stralfors A, Sorberg M, Wretlind B (2008) Role of outer membrane protein OprD and penicillin-binding proteins in resistance of Pseudomonas aeruginosa to imipenem and meropenem. Int J Antimicrob Agents 31:427–433PubMedCrossRefGoogle Scholar
  35. Fenollar-Ferrer C, Donoso J, Muà ± oz F, Frau J (2008) Evolution of class C Î2-lactamases: factors influencing their hydrolysis and recognition mechanisms. Theor Chem Accounts 121:209–218CrossRefGoogle Scholar
  36. Fernandez L, Hancock RE (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev Springer, New York 25:661–681Google Scholar
  37. Finberg RW, Guharoy R (2012) Monobactams. In: Clinical use of anti-infective agents Springer, New York pp 37–39Google Scholar
  38. Fox PM, Lampen RJ, Stumpf KS, Archer GL, Climo MW (2006) Successful therapy of experimental endocarditis caused by vancomycin-resistant Staphylococcus aureus with a combination of vancomycin and beta-lactam antibiotics. Antimicrob Agents Chemother 50:2951–2956PubMedPubMedCentralCrossRefGoogle Scholar
  39. Fuda C, Suvorov M, Vakulenko SB, Mobashery S (2004) The basis for resistance to beta-lactam antibiotics by penicillin-binding protein 2a of methicillin-resistant Staphylococcus aureus. J Biol Chem 279:40802–40806PubMedCrossRefGoogle Scholar
  40. Fuda C et al (2005) Activation for catalysis of penicillin-binding protein 2a from methicillin-resistant Staphylococcus aureus by bacterial cell wall. J Am Chem Soc 127:2056–2057PubMedCrossRefGoogle Scholar
  41. Galdiero S et al (2013) Microbe-host interactions: structure and role of Gram-negative bacterial porins. Curr Protein Pept Sci 13:843–854CrossRefGoogle Scholar
  42. Golemi D, Maveyraud L, Vakulenko S, Samama JP, Mobashery S (2001) Critical involvement of a carbamylated lysine in catalytic function of class D beta-lactamases. Proc Natl Acad Sci U S A 98:14280–14285PubMedPubMedCentralCrossRefGoogle Scholar
  43. Goodell EW (1985) Recycling of murein by Escherichia coli. J Bacteriol 163:305–310PubMedPubMedCentralGoogle Scholar
  44. Hackbarth CJ, Chambers HF (1993) blaI and blaR1 regulate beta-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 37:1144–1149PubMedPubMedCentralCrossRefGoogle Scholar
  45. Harder KJ, Nikaido H, Matsuhashi M (1981) Mutants of Escherichia coli that are resistant to certain beta-lactam compounds lack the ompF porin. Antimicrob Agents Chemother 20:549–552PubMedPubMedCentralCrossRefGoogle Scholar
  46. Heritier C, Poirel L, Lambert T, Nordmann P (2005) Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 49:3198–3202PubMedPubMedCentralCrossRefGoogle Scholar
  47. Hermann JC, Hensen C, Ridder L, Mulholland AJ, Holtje HD (2005) Mechanisms of antibiotic resistance: QM/MM modeling of the acylation reaction of a class A beta-lactamase with benzylpenicillin. J Am Chem Soc 127:4454–4465PubMedCrossRefGoogle Scholar
  48. Hernandez Valladares M et al (1997) Zn(II) dependence of the Aeromonas hydrophila AE036 metallo-beta-lactamase activity and stability. Biochemistry 36:11534–11541PubMedCrossRefGoogle Scholar
  49. Higgins MK, Bokma E, Koronakis E, Hughes C, Koronakis V (2004) Structure of the periplasmic component of a bacterial drug efflux pump. Proc Natl Acad Sci U S A 101:9994–9999PubMedPubMedCentralCrossRefGoogle Scholar
  50. Hinchliffe P, Symmons MF, Hughes C, Koronakis V (2013) Structure and operation of bacterial tripartite pumps. Annu Rev Microbiol 67:221–242PubMedCrossRefGoogle Scholar
  51. Huang H, Hancock RE (1996) The role of specific surface loop regions in determining the function of the imipenem-specific pore protein OprD of Pseudomonas aeruginosa. J Bacteriol 178:3085–3090PubMedPubMedCentralCrossRefGoogle Scholar
  52. Jacobs C, Huang LJ, Bartowsky E, Normark S, Park JT (1994) Bacterial cell wall recycling provides cytosolic muropeptides as effectors for beta-lactamase induction. EMBO J 13:4684–4694PubMedPubMedCentralGoogle Scholar
  53. Jacoby GA (2009) AmpC beta-lactamases. Clin Microbiol Rev 22:161–182, Table of ContentsPubMedPubMedCentralCrossRefGoogle Scholar
  54. Johnson JW, Fisher JF, Mobashery S (2012) Bacterial cell-wall recycling. Ann N Y Acad Sci 1277:54–75PubMedPubMedCentralCrossRefGoogle Scholar
  55. Jovetic S, Zhu Y, Marcone GL, Marinelli F, Tramper J (2010) beta-Lactam and glycopeptide antibiotics: first and last line of defense? Trends Biotechnol 28:596–604PubMedCrossRefGoogle Scholar
  56. Kaczmarek FS et al (2004) Genetic and molecular characterization of beta-lactamase-negative ampicillin-resistant Haemophilus influenzae with unusually high resistance to ampicillin. Antimicrob Agents Chemother 48:1630–1639PubMedPubMedCentralCrossRefGoogle Scholar
  57. Keefer CS, Blake FG, Marshall EK, Lockwood JS, Wood WB (1943) Penicillin in the treatment of infections. J Am Med Assoc 122:1217–1224CrossRefGoogle Scholar
  58. Keepers TR, Gomez M, Celeri C, Nichols WW, Krause KM (2014) Bactericidal activity, absence of serum effect, and time-kill kinetics of ceftazidime-avibactam against beta-lactamase-producing Enterobacteriaceae and Pseudomonas aeruginosa. Antimicrob Agents Chemother 58:5297–5305PubMedPubMedCentralCrossRefGoogle Scholar
  59. Kim C et al (2012) Properties of a novel PBP2A protein homolog from Staphylococcus aureus strain LGA251 and its contribution to the beta-lactam-resistant phenotype. J Biol Chem 287:36854–36863PubMedPubMedCentralCrossRefGoogle Scholar
  60. King DT, Strynadka NC (2012) Targeting metallo-beta-lactamase enzymes in antibiotic resistance. Future Med Chem 5:1243–1263CrossRefGoogle Scholar
  61. Koronakis V, Sharff A, Koronakis E, Luisi B, Hughes C (2000) Crystal structure of the bacterial membrane protein TolC central to multidrug efflux and protein export. Nature 405:914–919PubMedCrossRefGoogle Scholar
  62. Lambert PA (2005) Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev 57:1471–1485PubMedCrossRefGoogle Scholar
  63. Landman D et al (2014) In vitro activity of the siderophore monosulfactam BAL30072 against contemporary Gram-negative pathogens from New York City, including multidrug-resistant isolates. Int J Antimicrob Agents 43:527–532PubMedCrossRefGoogle Scholar
  64. Lewis K (1994) Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem Sci 19:119–123PubMedCrossRefGoogle Scholar
  65. Li XZ, Ma D, Livermore DM, Nikaido H (1994a) Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: active efflux as a contributing factor to beta-lactam resistance. Antimicrob Agents Chemother 38:1742–1752PubMedPubMedCentralCrossRefGoogle Scholar
  66. Li XZ, Livermore DM, Nikaido H (1994b) Role of efflux pump(s) in intrinsic resistance of Pseudomonas aeruginosa: resistance to tetracycline, chloramphenicol, and norfloxacin. Antimicrob Agents Chemother 38:1732–1741PubMedPubMedCentralCrossRefGoogle Scholar
  67. Lim D, Strynadka NC (2002) Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol 9:870–876PubMedGoogle Scholar
  68. Llarrull LI, Mobashery S (2012) Dissection of events in the resistance to beta-lactam antibiotics mediated by the protein BlaR1 from Staphylococcus aureus. Biochemistry 51:4642–4649PubMedPubMedCentralCrossRefGoogle Scholar
  69. Lomovskaya O, Zgurskaya HI, Totrov M, Watkins WJ (2007) Waltzing transporters and ‘the dance macabre’ between humans and bacteria. Nat Rev Drug Discov 6:56–65PubMedCrossRefGoogle Scholar
  70. Lou H et al (2011) Altered antibiotic transport in OmpC mutants isolated from a series of clinical strains of multi-drug resistant E. coli. PLoS One 6(e25825)Google Scholar
  71. Lovering AL, Safadi SS, Strynadka NC (2012) Structural perspective of peptidoglycan biosynthesis and assembly. Annu Rev Biochem 81:451–478PubMedCrossRefGoogle Scholar
  72. Macheboeuf P, Contreras-Martel C, Job V, Dideberg O, Dessen A (2006) Penicillin binding proteins: key players in bacterial cell cycle and drug resistance processes. FEMS Microbiol Rev 30:673–691PubMedCrossRefGoogle Scholar
  73. Majiduddin FK, Materon IC, Palzkill TG (2002) Molecular analysis of beta-lactamase structure and function. Int J Med Microbiol 292:127–137PubMedCrossRefGoogle Scholar
  74. Marrero A, Mallorqui-Fernandez G, Guevara T, Garcia-Castellanos R, Gomis-Ruth FX (2006) Unbound and acylated structures of the MecR1 extracellular antibiotic-sensor domain provide insights into the signal-transduction system that triggers methicillin resistance. J Mol Biol 361:506–521PubMedCrossRefGoogle Scholar
  75. Maveyraud L et al (1998) Structural basis for clinical longevity of carbapenem antibiotics in the face of challenge by the common class A Î2-lactamases from the antibiotic-resistant bacteria. J Am Chem Soc 120:9748–9752CrossRefGoogle Scholar
  76. McConeghy KW, Bleasdale SC, Rodvold KA (2013) The empirical combination of vancomycin and a beta-lactam for Staphylococcal bacteremia. Clin Infect Dis 57:1760–1765PubMedCrossRefGoogle Scholar
  77. McKinney TK, Sharma VK, Craig WA, Archer GL (2001) Transcription of the gene mediating methicillin resistance in Staphylococcus aureus (mecA) is corepressed but not coinduced by cognate mecA and beta-lactamase regulators. J Bacteriol 183:6862–6868PubMedPubMedCentralCrossRefGoogle Scholar
  78. Mikolosko J, Bobyk K, Zgurskaya HI, Ghosh P (2006) Conformational flexibility in the multidrug efflux system protein AcrA. Structure 14:577–587PubMedPubMedCentralCrossRefGoogle Scholar
  79. Milheirico C, Portelinha A, Krippahl L, de Lencastre H, Oliveira DC (2011) Evidence for a purifying selection acting on the beta-lactamase locus in epidemic clones of methicillin-resistant Staphylococcus aureus. BMC Microbiol 11:76PubMedPubMedCentralCrossRefGoogle Scholar
  80. Miller EL (2002) The penicillins: a review and update. J Midwifery Women’s Health 47:426–434CrossRefGoogle Scholar
  81. Mollmann U, Heinisch L, Bauernfeind A, Kohler T, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals 22:615–624PubMedCrossRefGoogle Scholar
  82. Murakami S, Nakashima R, Yamashita E, Yamaguchi A (2002) Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419:587–593PubMedCrossRefGoogle Scholar
  83. Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A (2006) Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443:173–179PubMedCrossRefGoogle Scholar
  84. Neu HC (1982) The new beta-lactamase-stable cephalosporins. Ann Intern Med 97:408–419PubMedCrossRefGoogle Scholar
  85. Nikaido H, Takatsuka Y (2009) Mechanisms of RND multidrug efflux pumps. Biochim Biophys Acta 1794:769–781PubMedCrossRefGoogle Scholar
  86. Nordmann P, Cuzon G, Naas T (2009) The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 9:228–236PubMedCrossRefGoogle Scholar
  87. Nordmann P, Poirel L, Walsh TR, Livermore DM (2011) The emerging NDM carbapenemases. Trends Microbiol 19:588–595PubMedCrossRefGoogle Scholar
  88. Ochs MM, McCusker MP, Bains M, Hancock RE (1999) Negative regulation of the Pseudomonas aeruginosa outer membrane porin OprD selective for imipenem and basic amino acids. Antimicrob Agents Chemother 43:1085–1090PubMedPubMedCentralGoogle Scholar
  89. Okamoto T et al (2002) A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother 50:849–856PubMedCrossRefGoogle Scholar
  90. Otero LH et al (2013) How allosteric control of Staphylococcus aureus penicillin binding protein 2a enables methicillin resistance and physiological function. Proc Natl Acad Sci U S A 110:16808–16813PubMedPubMedCentralCrossRefGoogle Scholar
  91. Paetzel M et al (2000) Crystal structure of the class D beta-lactamase OXA-10. Nat Struct Biol 7:918–925PubMedCrossRefGoogle Scholar
  92. Page MGP (2000) Beta-lactamase inhibitors. Drug Resist Updat 3:109–125PubMedCrossRefGoogle Scholar
  93. Page MGP (2012) β-lactam antibiotics. In: Dougherty TJ and Pucci MJ (ed) Antibiot Discov Dev Springer, New York, 79–117Google Scholar
  94. Page MI, Badarau A (2008) The mechanisms of catalysis by metallo beta-lactamases. Bioinorg Chem Appl 576297 10.1155/2008/576297Google Scholar
  95. Pages JM et al (2009) Efflux pump, the masked side of beta-lactam resistance in Klebsiella pneumoniae clinical isolates. PLoS One 4:e4817PubMedPubMedCentralCrossRefGoogle Scholar
  96. Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (2011) Carbapenems: past, present, and future. Antimicrob Agents Chemother 55:4943–4960PubMedPubMedCentralCrossRefGoogle Scholar
  97. Payne DJ, Cramp R, Winstanley DJ, Knowles DJ (1994) Comparative activities of clavulanic acid, sulbactam, and tazobactam against clinically important beta-lactamases. Antimicrob Agents Chemother 38:767–772PubMedPubMedCentralCrossRefGoogle Scholar
  98. Pernot L et al (2004) A PBP2x from a clinical isolate of Streptococcus pneumoniae exhibits an alternative mechanism for reduction of susceptibility to beta-lactam antibiotics. J Biol Chem 279:16463–16470PubMedCrossRefGoogle Scholar
  99. Philippon A, Arlet G, Jacoby GA (2002) Plasmid-determined AmpC-type beta-lactamases. Antimicrob Agents Chemother 46:1–11PubMedPubMedCentralCrossRefGoogle Scholar
  100. Pinho MG, de Lencastre H, Tomasz A (2001) An acquired and a native penicillin-binding protein cooperate in building the cell wall of drug-resistant staphylococci. Proc Natl Acad Sci U S A 98:10886–10891PubMedPubMedCentralCrossRefGoogle Scholar
  101. Poirel L, Potron A, Nordmann P (2012) OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother 67:1597–1606PubMedCrossRefGoogle Scholar
  102. Pos KM (2009) Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 1794:782–793PubMedCrossRefGoogle Scholar
  103. Queenan AM, Shang W, Flamm R, Bush K (2009) Hydrolysis and inhibition profiles of beta-lactamases from molecular classes A to D with doripenem, imipenem, and meropenem. Antimicrob Agents Chemother 54:565–569PubMedPubMedCentralCrossRefGoogle Scholar
  104. Reith J, Mayer C (2011) Peptidoglycan turnover and recycling in Gram-positive bacteria. Appl Microbiol Biotechnol 92:1–11PubMedCrossRefGoogle Scholar
  105. Rolinson GN, Geddes AM (2007) The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA). Int J Antimicrob Agents 29:3–8PubMedCrossRefGoogle Scholar
  106. Ropp PA, Hu M, Olesky M, Nicholas RA (2002) Mutations in ponA, the gene encoding penicillin-binding protein 1, and a novel locus, penC, are required for high-level chromosomally mediated penicillin resistance in Neisseria gonorrhoeae. Antimicrob Agents Chemother 46:769–777PubMedPubMedCentralCrossRefGoogle Scholar
  107. Ryffel C, Kayser FH, Berger-Bachi B (1992) Correlation between regulation of mecA transcription and expression of methicillin resistance in staphylococci. Antimicrob Agents Chemother 36:25–31PubMedPubMedCentralCrossRefGoogle Scholar
  108. Sabath LD, Abraham EP (1966) Zinc as a cofactor for cephalosporinase from Bacillus cereus 569. Biochem J 98:11C–13CPubMedPubMedCentralCrossRefGoogle Scholar
  109. Sader HS, Farrell DJ, Castanheira M, Flamm RK, Jones RN (2014) Antimicrobial activity of ceftolozane/tazobactam tested against Pseudomonas aeruginosa and Enterobacteriaceae with various resistance patterns isolated in European hospitals (2011–12). J Antimicrob Chemother 69:2713–2722PubMedCrossRefGoogle Scholar
  110. Saha R, Saha N, Donofrio RS, Bestervelt LL (2012) Microbial siderophores: a mini review. J Basic Microbiol 53:303–317PubMedCrossRefGoogle Scholar
  111. Sauvage E et al (2002) The 2.4-A crystal structure of the penicillin-resistant penicillin-binding protein PBP5fm from Enterococcus faecium in complex with benzylpenicillin. Cell Mol Life Sci 59:1223–1232PubMedCrossRefGoogle Scholar
  112. Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P (2008) The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev 32:234–258PubMedCrossRefGoogle Scholar
  113. Seeger MA et al (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313:1295–1298PubMedCrossRefGoogle Scholar
  114. Shore AC, Coleman DC (2013) Staphylococcal cassette chromosome mec: recent advances and new insights. Int J Med Microbiol 303:350–359PubMedCrossRefGoogle Scholar
  115. Strynadka NC et al (1992) Molecular structure of the acyl-enzyme intermediate in beta-lactam hydrolysis at 1.7 A resolution. Nature 359:700–705PubMedCrossRefGoogle Scholar
  116. Strynadka NC, Martin R, Jensen SE, Gold M, Jones JB (1996) Structure-based design of a potent transition state analogue for TEM-1 beta-lactamase. Nat Struct Biol 3:688–695PubMedCrossRefGoogle Scholar
  117. Su CC et al (2011) Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature 470:558–562PubMedPubMedCentralCrossRefGoogle Scholar
  118. Swaren P et al (1995) Electrostatic analysis of TEM1 beta-lactamase: effect of substrate binding, steep potential gradients and consequences of site-directed mutations. Structure 3:603–613PubMedCrossRefGoogle Scholar
  119. Symmons MF, Bokma E, Koronakis E, Hughes C, Koronakis V (2009) The assembled structure of a complete tripartite bacterial multidrug efflux pump. Proc Natl Acad Sci U S A 106:7173–7178PubMedPubMedCentralCrossRefGoogle Scholar
  120. Szarecka A, Lesnock KR, Ramirez-Mondragon CA, Nicholas HB Jr, Wymore T (2011) The Class D beta-lactamase family: residues governing the maintenance and diversity of function. Protein Eng Des Sel 24:801–809PubMedPubMedCentralCrossRefGoogle Scholar
  121. Tipper DJ, Strominger JL (1965) Mechanism of action of penicillins: a proposal based on their structural similarity to acyl-d-alanyl-d-alanine. Proc Natl Acad Sci U S A 54:1133–1141PubMedPubMedCentralCrossRefGoogle Scholar
  122. Tsubakishita S, Kuwahara-Arai K, Baba T, Hiramatsu K (2010) Staphylococcal cassette chromosome mec-like element in Macrococcus caseolyticus. Antimicrob Agents Chemother 54:1469–1475PubMedPubMedCentralCrossRefGoogle Scholar
  123. Turner PJ (2005) Extended-spectrum beta-lactamases. Clin Infect Dis 41(Suppl 4):S273–S275PubMedCrossRefGoogle Scholar
  124. Typas A, Banzhaf M, Gross CA, Vollmer W (2011) From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nat Rev Microbiol 10:123–136PubMedPubMedCentralGoogle Scholar
  125. Vercheval L et al (2010) Three factors that modulate the activity of class D beta-lactamases and interfere with the post-translational carboxylation of Lys70. Biochem J 432:495–504PubMedCrossRefGoogle Scholar
  126. Walsh TR (2010) Emerging carbapenemases: a global perspective. Int J Antimicrob Agents 36(Suppl 3):S8–S14PubMedCrossRefGoogle Scholar
  127. Walsh TR, Toleman MA, Poirel L, Nordmann P (2005) Metallo-beta-lactamases: the quiet before the storm? Clin Microbiol Rev 18:306–325PubMedPubMedCentralCrossRefGoogle Scholar
  128. Wang Z, Fast W, Valentine AM, Benkovic SJ (1999) Metallo-beta-lactamase: structure and mechanism. Curr Opin Chem Biol 3:614–622PubMedCrossRefGoogle Scholar
  129. Waxman DJ, Strominger JL (1983) Penicillin-binding proteins and the mechanism of action of beta-lactam antibiotics. Annu Rev Biochem 52:825–869PubMedCrossRefGoogle Scholar
  130. Wilke MS, Hills TL, Zhang HZ, Chambers HF, Strynadka NC (2004) Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus. J Biol Chem 279:47278–47287PubMedCrossRefGoogle Scholar
  131. Wise EM Jr, Park JT (1965) Penicillin: its basic site of action as an inhibitor of a peptide cross-linking reaction in cell wall mucopeptide synthesis. Proc Natl Acad Sci U S A 54:75–81PubMedPubMedCentralCrossRefGoogle Scholar
  132. Xu D, Xie D, Guo H (2006) Catalytic mechanism of class B2 metallo-beta-lactamase. J Biol Chem 281:8740–8747PubMedCrossRefGoogle Scholar
  133. Yao Z, Kahne D, Kishony R (2012) Distinct single-cell morphological dynamics under beta-lactam antibiotics. Mol Cell 48:705–712PubMedPubMedCentralCrossRefGoogle Scholar
  134. Yong D et al (2009) Characterization of a new metallo-beta-lactamase gene, bla(NDM-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 53:5046–5054PubMedPubMedCentralCrossRefGoogle Scholar
  135. Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF (2001) A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science 291:1962–1965PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Dustin T. King
    • 1
  • Solmaz Sobhanifar
    • 1
  • Natalie C. J. Strynadka
    • 1
    Email author
  1. 1.Department of Biochemistry and Molecular Biology and Center for Blood ResearchUniversity of British ColumbiaVancouverCanada

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