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The Mechanisms of Resistance to β-Lactam Antibiotics

  • Living reference work entry
  • First Online:
Handbook of Antimicrobial Resistance

Abstract

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.

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References

  • 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 67:473–477

    PubMed  Google Scholar 

  • Abraham EP, Chain E (1988) An enzyme from bacteria able to destroy penicillin. 1940. Rev Infect Dis 10:677–678

    CAS  PubMed  Google Scholar 

  • Amaral L, Molnar J (2012) Potential therapy of multidrug-resistant and extremely drug-resistant tuberculosis with thioridazine. In Vivo 26:231–236

    CAS  PubMed  Google Scholar 

  • 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 9:816–819

    CAS  PubMed  Google Scholar 

  • Amoroso A et al (2012) A peptidoglycan fragment triggers beta-lactam resistance in Bacillus licheniformis. PLoS Pathog 8:e1002571

    CAS  PubMed Central  PubMed  Google Scholar 

  • Andersen C et al (2002) Transition to the open state of the TolC periplasmic tunnel entrance. Proc Natl Acad Sci U S A 99:11103–11108

    CAS  PubMed Central  PubMed  Google Scholar 

  • Archer GL, Niemeyer DM, Thanassi JA, Pucci MJ (1994) Dissemination among staphylococci of DNA sequences associated with methicillin resistance. Antimicrob Agents Chemother 38:447–454

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 191:1180–1190

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bavro VN et al (2008) Assembly and channel opening in a bacterial drug efflux machine. Mol Cell 30:114–121

    CAS  PubMed Central  PubMed  Google Scholar 

  • Bebrone C (2007) Metallo-beta-lactamases (classification, activity, genetic organization, structure, zinc coordination) and their superfamily. Biochem Pharmacol 74:1686–1701

    CAS  PubMed  Google Scholar 

  • 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 53:4464–4471

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 126:13945–13947

    CAS  PubMed  Google Scholar 

  • 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 78:3–21

    CAS  PubMed  Google Scholar 

  • Bonfiglio G, Russo G, Nicoletti G (2002) Recent developments in carbapenems. Expert Opin Investig Drugs 11:529–544

    CAS  PubMed  Google Scholar 

  • 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 176:333–337

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 4:913–919

    CAS  PubMed  Google Scholar 

  • Brown MH, Paulsen IT, Skurray RA (1999) The multidrug efflux protein NorM is a prototype of a new family of transporters. Mol Microbiol 31:394–395

    CAS  PubMed  Google Scholar 

  • 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 427–453

    Google Scholar 

  • Bush K (2013) Proliferation and significance of clinically relevant beta-lactamases. Ann N Y Acad Sci 1277:84–90

    CAS  PubMed  Google Scholar 

  • Bush K, Macielag MJ (2010) New beta-lactam antibiotics and beta-lactamase inhibitors. Expert Opin Ther Pat 20:1277–1293

    CAS  PubMed  Google Scholar 

  • Buynak JD (2013) beta-Lactamase inhibitors: a review of the patent literature (2010–2013). Expert Opin Ther Pat 23:1469–1481

    CAS  PubMed  Google Scholar 

  • 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 20:436–440

    CAS  PubMed  Google Scholar 

  • 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 129:3834–3835

    CAS  PubMed  Google Scholar 

  • 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 46:7822–7831

    CAS  PubMed  Google Scholar 

  • 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 46:2208–2218

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 276:45065–45078

    PubMed  Google Scholar 

  • Delmas J et al (2010) Structural insights into substrate recognition and product expulsion in CTX-M enzymes. J Mol Biol 400:108–120

    CAS  PubMed  Google Scholar 

  • Deng X et al (2012) Expression of multidrug resistance efflux pump gene norA is iron responsive in Staphylococcus aureus. J Bacteriol 194:1753–1762

    CAS  PubMed Central  PubMed  Google Scholar 

  • Docquier JD et al (2009) Crystal structure of the OXA-48 beta-lactamase reveals mechanistic diversity among class D carbapenemases. Chem Biol 16:540–547

    CAS  PubMed  Google Scholar 

  • 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 63:659–667

    CAS  PubMed  Google Scholar 

  • Dowson CG, Coffey TJ, Spratt BG (1994) Origin and molecular epidemiology of penicillin-binding-protein-mediated resistance to beta-lactam antibiotics. Trends Microbiol 2:361–366

    CAS  PubMed  Google Scholar 

  • Duguid JP (1946) The sensitivity of bacteria to the action of penicillin. Edinb Med J 53:401–412

    CAS  PubMed  Google Scholar 

  • 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–S353

    CAS  PubMed  Google Scholar 

  • 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 31:427–433

    CAS  PubMed  Google Scholar 

  • 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 121:209–218

    CAS  Google Scholar 

  • Fernandez L, Hancock RE (2012) Adaptive and mutational resistance: role of porins and efflux pumps in drug resistance. Clin Microbiol Rev Springer, New York 25:661–681

    Google Scholar 

  • Finberg RW, Guharoy R (2012) Monobactams. In: Clinical use of anti-infective agents Springer, New York pp 37–39

    Google Scholar 

  • 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 50:2951–2956

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 279:40802–40806

    CAS  PubMed  Google Scholar 

  • 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 127:2056–2057

    CAS  PubMed  Google Scholar 

  • Galdiero S et al (2013) Microbe-host interactions: structure and role of Gram-negative bacterial porins. Curr Protein Pept Sci 13:843–854

    Google Scholar 

  • 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 98:14280–14285

    CAS  PubMed Central  PubMed  Google Scholar 

  • Goodell EW (1985) Recycling of murein by Escherichia coli. J Bacteriol 163:305–310

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hackbarth CJ, Chambers HF (1993) blaI and blaR1 regulate beta-lactamase and PBP 2a production in methicillin-resistant Staphylococcus aureus. Antimicrob Agents Chemother 37:1144–1149

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 20:549–552

    CAS  PubMed Central  PubMed  Google Scholar 

  • Heritier C, Poirel L, Lambert T, Nordmann P (2005) Contribution of acquired carbapenem-hydrolyzing oxacillinases to carbapenem resistance in Acinetobacter baumannii. Antimicrob Agents Chemother 49:3198–3202

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 127:4454–4465

    CAS  PubMed  Google Scholar 

  • Hernandez Valladares M et al (1997) Zn(II) dependence of the Aeromonas hydrophila AE036 metallo-beta-lactamase activity and stability. Biochemistry 36:11534–11541

    CAS  PubMed  Google Scholar 

  • 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 101:9994–9999

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hinchliffe P, Symmons MF, Hughes C, Koronakis V (2013) Structure and operation of bacterial tripartite pumps. Annu Rev Microbiol 67:221–242

    CAS  PubMed  Google Scholar 

  • 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 178:3085–3090

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 13:4684–4694

    CAS  PubMed Central  PubMed  Google Scholar 

  • Jacoby GA (2009) AmpC beta-lactamases. Clin Microbiol Rev 22:161–182, Table of Contents

    CAS  PubMed Central  PubMed  Google Scholar 

  • Johnson JW, Fisher JF, Mobashery S (2012) Bacterial cell-wall recycling. Ann N Y Acad Sci 1277:54–75

    PubMed Central  PubMed  Google Scholar 

  • Jovetic S, Zhu Y, Marcone GL, Marinelli F, Tramper J (2010) beta-Lactam and glycopeptide antibiotics: first and last line of defense? Trends Biotechnol 28:596–604

    CAS  PubMed  Google Scholar 

  • 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 48:1630–1639

    CAS  PubMed Central  PubMed  Google Scholar 

  • Keefer CS, Blake FG, Marshall EK, Lockwood JS, Wood WB (1943) Penicillin in the treatment of infections. J Am Med Assoc 122:1217–1224

    CAS  Google Scholar 

  • 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 58:5297–5305

    CAS  PubMed  Google Scholar 

  • 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 287:36854–36863

    CAS  PubMed Central  PubMed  Google Scholar 

  • King DT, Strynadka NC (2012) Targeting metallo-beta-lactamase enzymes in antibiotic resistance. Future Med Chem 5:1243–1263

    Google Scholar 

  • 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 405:914–919

    CAS  PubMed  Google Scholar 

  • Lambert PA (2005) Bacterial resistance to antibiotics: modified target sites. Adv Drug Deliv Rev 57:1471–1485

    CAS  PubMed  Google Scholar 

  • 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 43:527–532

    CAS  PubMed  Google Scholar 

  • Lewis K (1994) Multidrug resistance pumps in bacteria: variations on a theme. Trends Biochem Sci 19:119–123

    CAS  PubMed  Google Scholar 

  • 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 38:1742–1752

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 38:1732–1741

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lim D, Strynadka NC (2002) Structural basis for the beta lactam resistance of PBP2a from methicillin-resistant Staphylococcus aureus. Nat Struct Biol 9:870–876

    CAS  PubMed  Google Scholar 

  • Llarrull LI, Mobashery S (2012) Dissection of events in the resistance to beta-lactam antibiotics mediated by the protein BlaR1 from Staphylococcus aureus. Biochemistry 51:4642–4649

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lomovskaya O, Zgurskaya HI, Totrov M, Watkins WJ (2007) Waltzing transporters and ‘the dance macabre’ between humans and bacteria. Nat Rev Drug Discov 6:56–65

    CAS  PubMed  Google Scholar 

  • 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 

  • Lovering AL, Safadi SS, Strynadka NC (2012) Structural perspective of peptidoglycan biosynthesis and assembly. Annu Rev Biochem 81:451–478

    CAS  PubMed  Google Scholar 

  • 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 30:673–691

    CAS  PubMed  Google Scholar 

  • Majiduddin FK, Materon IC, Palzkill TG (2002) Molecular analysis of beta-lactamase structure and function. Int J Med Microbiol 292:127–137

    CAS  PubMed  Google Scholar 

  • 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 361:506–521

    CAS  PubMed  Google Scholar 

  • 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 120:9748–9752

    CAS  Google Scholar 

  • McConeghy KW, Bleasdale SC, Rodvold KA (2013) The empirical combination of vancomycin and a beta-lactam for Staphylococcal bacteremia. Clin Infect Dis 57:1760–1765

    PubMed  Google Scholar 

  • 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 183:6862–6868

    CAS  PubMed Central  PubMed  Google Scholar 

  • Mikolosko J, Bobyk K, Zgurskaya HI, Ghosh P (2006) Conformational flexibility in the multidrug efflux system protein AcrA. Structure 14:577–587

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 11:76

    CAS  PubMed Central  PubMed  Google Scholar 

  • Miller EL (2002) The penicillins: a review and update. J Midwifery Women’s Health 47:426–434

    Google Scholar 

  • Mollmann U, Heinisch L, Bauernfeind A, Kohler T, Ankel-Fuchs D (2009) Siderophores as drug delivery agents: application of the “Trojan Horse” strategy. Biometals 22:615–624

    PubMed  Google Scholar 

  • Murakami S, Nakashima R, Yamashita E, Yamaguchi A (2002) Crystal structure of bacterial multidrug efflux transporter AcrB. Nature 419:587–593

    CAS  PubMed  Google Scholar 

  • Murakami S, Nakashima R, Yamashita E, Matsumoto T, Yamaguchi A (2006) Crystal structures of a multidrug transporter reveal a functionally rotating mechanism. Nature 443:173–179

    CAS  PubMed  Google Scholar 

  • Neu HC (1982) The new beta-lactamase-stable cephalosporins. Ann Intern Med 97:408–419

    CAS  PubMed  Google Scholar 

  • Nikaido H, Takatsuka Y (2009) Mechanisms of RND multidrug efflux pumps. Biochim Biophys Acta 1794:769–781

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nordmann P, Cuzon G, Naas T (2009) The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria. Lancet Infect Dis 9:228–236

    CAS  PubMed  Google Scholar 

  • Nordmann P, Poirel L, Walsh TR, Livermore DM (2011) The emerging NDM carbapenemases. Trends Microbiol 19:588–595

    CAS  PubMed  Google Scholar 

  • 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 43:1085–1090

    CAS  PubMed Central  PubMed  Google Scholar 

  • Okamoto T et al (2002) A change in PBP1 is involved in amoxicillin resistance of clinical isolates of Helicobacter pylori. J Antimicrob Chemother 50:849–856

    CAS  PubMed  Google Scholar 

  • 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 110:16808–16813

    PubMed Central  PubMed  Google Scholar 

  • Paetzel M et al (2000) Crystal structure of the class D beta-lactamase OXA-10. Nat Struct Biol 7:918–925

    CAS  PubMed  Google Scholar 

  • Page MGP (2000) Beta-lactamase inhibitors. Drug Resist Updat 3:109–125

    CAS  PubMed  Google Scholar 

  • Page MGP (2012) β-lactam antibiotics. In: Dougherty TJ and Pucci MJ (ed) Antibiot Discov Dev Springer, New York, 79–117

    Google Scholar 

  • Page MI, Badarau A (2008) The mechanisms of catalysis by metallo beta-lactamases. Bioinorg Chem Appl 576297 10.1155/2008/576297

    Google Scholar 

  • Pages JM et al (2009) Efflux pump, the masked side of beta-lactam resistance in Klebsiella pneumoniae clinical isolates. PLoS One 4:e4817

    PubMed Central  PubMed  Google Scholar 

  • Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA (2011) Carbapenems: past, present, and future. Antimicrob Agents Chemother 55:4943–4960

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 38:767–772

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 279:16463–16470

    CAS  PubMed  Google Scholar 

  • Philippon A, Arlet G, Jacoby GA (2002) Plasmid-determined AmpC-type beta-lactamases. Antimicrob Agents Chemother 46:1–11

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 98:10886–10891

    CAS  PubMed Central  PubMed  Google Scholar 

  • Poirel L, Potron A, Nordmann P (2012) OXA-48-like carbapenemases: the phantom menace. J Antimicrob Chemother 67:1597–1606

    CAS  PubMed  Google Scholar 

  • Pos KM (2009) Drug transport mechanism of the AcrB efflux pump. Biochim Biophys Acta 1794:782–793

    CAS  PubMed  Google Scholar 

  • 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 54:565–569

    PubMed Central  PubMed  Google Scholar 

  • Reith J, Mayer C (2011) Peptidoglycan turnover and recycling in Gram-positive bacteria. Appl Microbiol Biotechnol 92:1–11

    CAS  PubMed  Google Scholar 

  • Rolinson GN, Geddes AM (2007) The 50th anniversary of the discovery of 6-aminopenicillanic acid (6-APA). Int J Antimicrob Agents 29:3–8

    CAS  PubMed  Google Scholar 

  • 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 46:769–777

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ryffel C, Kayser FH, Berger-Bachi B (1992) Correlation between regulation of mecA transcription and expression of methicillin resistance in staphylococci. Antimicrob Agents Chemother 36:25–31

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sabath LD, Abraham EP (1966) Zinc as a cofactor for cephalosporinase from Bacillus cereus 569. Biochem J 98:11C–13C

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 69:2713–2722

    PubMed  Google Scholar 

  • Saha R, Saha N, Donofrio RS, Bestervelt LL (2012) Microbial siderophores: a mini review. J Basic Microbiol 53:303–317

    PubMed  Google Scholar 

  • 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 59:1223–1232

    CAS  PubMed  Google Scholar 

  • Sauvage E, Kerff F, Terrak M, Ayala JA, Charlier P (2008) The penicillin-binding proteins: structure and role in peptidoglycan biosynthesis. FEMS Microbiol Rev 32:234–258

    CAS  PubMed  Google Scholar 

  • Seeger MA et al (2006) Structural asymmetry of AcrB trimer suggests a peristaltic pump mechanism. Science 313:1295–1298

    CAS  PubMed  Google Scholar 

  • Shore AC, Coleman DC (2013) Staphylococcal cassette chromosome mec: recent advances and new insights. Int J Med Microbiol 303:350–359

    CAS  PubMed  Google Scholar 

  • Strynadka NC et al (1992) Molecular structure of the acyl-enzyme intermediate in beta-lactam hydrolysis at 1.7 A resolution. Nature 359:700–705

    CAS  PubMed  Google Scholar 

  • 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 3:688–695

    CAS  PubMed  Google Scholar 

  • Su CC et al (2011) Crystal structure of the CusBA heavy-metal efflux complex of Escherichia coli. Nature 470:558–562

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 3:603–613

    CAS  PubMed  Google Scholar 

  • 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 106:7173–7178

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 24:801–809

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 54:1133–1141

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tsubakishita S, Kuwahara-Arai K, Baba T, Hiramatsu K (2010) Staphylococcal cassette chromosome mec-like element in Macrococcus caseolyticus. Antimicrob Agents Chemother 54:1469–1475

    CAS  PubMed Central  PubMed  Google Scholar 

  • Turner PJ (2005) Extended-spectrum beta-lactamases. Clin Infect Dis 41(Suppl 4):S273–S275

    CAS  PubMed  Google Scholar 

  • Typas A, Banzhaf M, Gross CA, Vollmer W (2011) From the regulation of peptidoglycan synthesis to bacterial growth and morphology. Nat Rev Microbiol 10:123–136

    PubMed  Google Scholar 

  • 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 432:495–504

    CAS  PubMed  Google Scholar 

  • Walsh TR (2010) Emerging carbapenemases: a global perspective. Int J Antimicrob Agents 36(Suppl 3):S8–S14

    CAS  PubMed  Google Scholar 

  • Walsh TR, Toleman MA, Poirel L, Nordmann P (2005) Metallo-beta-lactamases: the quiet before the storm? Clin Microbiol Rev 18:306–325

    CAS  PubMed Central  PubMed  Google Scholar 

  • Wang Z, Fast W, Valentine AM, Benkovic SJ (1999) Metallo-beta-lactamase: structure and mechanism. Curr Opin Chem Biol 3:614–622

    CAS  PubMed  Google Scholar 

  • Waxman DJ, Strominger JL (1983) Penicillin-binding proteins and the mechanism of action of beta-lactam antibiotics. Annu Rev Biochem 52:825–869

    CAS  PubMed  Google Scholar 

  • 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 279:47278–47287

    CAS  PubMed  Google Scholar 

  • 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 54:75–81

    CAS  PubMed Central  PubMed  Google Scholar 

  • Xu D, Xie D, Guo H (2006) Catalytic mechanism of class B2 metallo-beta-lactamase. J Biol Chem 281:8740–8747

    CAS  PubMed  Google Scholar 

  • Yao Z, Kahne D, Kishony R (2012) Distinct single-cell morphological dynamics under beta-lactam antibiotics. Mol Cell 48:705–712

    CAS  PubMed Central  PubMed  Google Scholar 

  • 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 53:5046–5054

    CAS  PubMed Central  PubMed  Google Scholar 

  • Zhang HZ, Hackbarth CJ, Chansky KM, Chambers HF (2001) A proteolytic transmembrane signaling pathway and resistance to beta-lactams in staphylococci. Science 291:1962–1965

    CAS  PubMed  Google Scholar 

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Acknowledgements

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).

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    Authors and Affiliations

    1. Department of Biochemistry and Molecular Biology and Center for Blood Research, University of British Columbia, 2350 Health Sciences Mall, V6T 1Z3, Vancouver, BC, Canada

      Dustin T. King, Solmaz Sobhanifar & Natalie C. J. Strynadka

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    1. Dustin T. King
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    2. Solmaz Sobhanifar
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    3. Natalie C. J. Strynadka
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    Correspondence to Natalie C. J. Strynadka .

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    1. McGill University, Montreal, Québec, Canada

      Matthias Gotte

    2. McGill University, Montreal, Canada

      Albert Berghuis

    3. McGill University, Montreal, Canada

      Greg Matlashewski

    4. McGill University, Montreal, Canada

      Mark Wainberg

    5. McGill University, Montreal, Canada

      Donald Sheppard

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    King, D.T., Sobhanifar, S., Strynadka, N.C.J. (2014). The Mechanisms of Resistance to β-Lactam Antibiotics. In: Gotte, M., Berghuis, A., Matlashewski, G., Wainberg, M., Sheppard, D. (eds) Handbook of Antimicrobial Resistance. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-0667-3_10-1

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    • DOI: https://doi.org/10.1007/978-1-4939-0667-3_10-1

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    • Online ISBN: 978-1-4939-0667-3

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