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Category: Bacterial Pathogenesis
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases, Page 1 of 2
< Previous page | Next page > /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap12-1.gif /docserver/preview/fulltext/10.1128/9781555817794/9781555812584_Chap12-2.gifAbstract:
The expanding problem of resistance to β-lactam antibiotics and β-lactam inhibitors of β-lactamases illustrates the genetic adaptability of bacterial populations. The evolution of bacterial resistance to the action of these drugs occurred over a relatively short period. Bacteria become resistant to antibiotics and β-lactam compounds acting as β-lactamase inhibitors either through mutations or by acquisition of specific resistance genes from other bacteria. Global antibacterial resistance is an increasing public health problem. The pharmaceutical industries are reacting to the problem by discovering novel antibacterial agents to overcome the emergence of bacterial resistance to antibiotics and β-lactamase inhibitors. A section of the chapter summarizes the status of the development of structural modifications of existing groups and subgroups of antibacterial agents to make them less susceptible to degradation by β-lactamases, to increase penetrability through the outer membrane of gram-negative bacteria, or to have an increased affinity for mutated penicillin-binding proteins (PBPs). The search for new anti-methicillin-resistant Staphylococcus aureus (MRSA)-lactam antibiotics appears to be focused on developing agents that inhibit PBP2a, which gives rise to methicillin resistance in staphylococci and penicillin-resistant pneumococci. The increase in β-lactam antibiotic resistance due to the production and rapid spread of resistance encoded by plasmids or transposons in pathogenic bacteria has made the enzymes an attractive target for drug development.
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Molecular organization of the approximately 50-kb mec region and its chromosomal location relative to fem factors and pur-nov-his. IS indicates IS431 elements flanking the tobramycin resistance plasmid pUB110. Tn554 is a transposon containing ermA, encoding inducible erythromycin resistance. Reprinted from H. F. Chambers, Clin. Microbiol. Rev. 10:781–791, with permission from the American Society for Microbiology
Molecular organization of the approximately 50-kb mec region and its chromosomal location relative to fem factors and pur-nov-his. IS indicates IS431 elements flanking the tobramycin resistance plasmid pUB110. Tn554 is a transposon containing ermA, encoding inducible erythromycin resistance. Reprinted from H. F. Chambers, Clin. Microbiol. Rev. 10:781–791, with permission from the American Society for Microbiology
Sites of peptidoglycan precursor synthesis at which blocks occur in fem mutants. UDP-Mur, uridine diphosphomuramyl peptide precursors; NAG-NAM, N-acetylglucosamine-Nacetylmuramic acid disaccharide (not shown in figure).
Sites of peptidoglycan precursor synthesis at which blocks occur in fem mutants. UDP-Mur, uridine diphosphomuramyl peptide precursors; NAG-NAM, N-acetylglucosamine-Nacetylmuramic acid disaccharide (not shown in figure).
Induction of β-lactamase synthesis in the C. freundii 382 010 mutant by β-Lactam antibiotics. Reprinted from P. Stapleton, K. Shannon, and I. Phillips, J. Antimicrob. Chemother. 36:483–496, 1995, with permission from the publisher.
Induction of β-lactamase synthesis in the C. freundii 382 010 mutant by β-Lactam antibiotics. Reprinted from P. Stapleton, K. Shannon, and I. Phillips, J. Antimicrob. Chemother. 36:483–496, 1995, with permission from the publisher.
Hypothetical model for β-lactamase induction in gram-negative bacteria. BL, β-Lactam; PG, peptidoglycan; G, AmpG; R, repressor form of AmpR; A, activator form of AmpR; D, AmpD; E, AmpE. For details, see the text. Reprinted from P. M. Bennett and I. Chopra, Antimicrob. Agents Chemother. 37:153–159, 1993, with permission from the American Society for Microbiology.
Hypothetical model for β-lactamase induction in gram-negative bacteria. BL, β-Lactam; PG, peptidoglycan; G, AmpG; R, repressor form of AmpR; A, activator form of AmpR; D, AmpD; E, AmpE. For details, see the text. Reprinted from P. M. Bennett and I. Chopra, Antimicrob. Agents Chemother. 37:153–159, 1993, with permission from the American Society for Microbiology.
Chemical structure of the cephalosporin BMS-247243.
Chemical structure of the cephalosporin BMS-247243.
Chemical structure of the β-methylcarbapenem L-786,392 (synthesized at Merck) and illustration of the releasable-hapten hypothesis. Nuc, nucleophile that could be the hydroxyl group of the serine PBPs.
Chemical structure of the β-methylcarbapenem L-786,392 (synthesized at Merck) and illustration of the releasable-hapten hypothesis. Nuc, nucleophile that could be the hydroxyl group of the serine PBPs.
Chemical structure of SM-17466.
Chemical structure of SM-17466.
Structure 1a is the general chemical structure of trinems. Structure 1b is the chemical structure of sanfetrinem and the ester sanfetrinem cilexetil.
Structure 1a is the general chemical structure of trinems. Structure 1b is the chemical structure of sanfetrinem and the ester sanfetrinem cilexetil.
Chemical structures of novel trinems synthesized at Sankyo Laboratories.
Chemical structures of novel trinems synthesized at Sankyo Laboratories.
Chemical structure of LB-10517.
Chemical structure of LB-10517.
Chemical structure of BMS-180680.
Chemical structure of BMS-180680.
Chemical structure of a rhodanine synthesized at Johnson Pharmaceutical.
Chemical structure of a rhodanine synthesized at Johnson Pharmaceutical.
Chemical structures of 3-substituted 7-(alkylidene) cephalosporin sulfones and 6-alkylidene-2′β-substituted penam sulfones.
Chemical structures of 3-substituted 7-(alkylidene) cephalosporin sulfones and 6-alkylidene-2′β-substituted penam sulfones.
Chemical structure of compound 1 synthesized by Bitha et al. at Wyeth-Ayerst.
Chemical structure of compound 1 synthesized by Bitha et al. at Wyeth-Ayerst.
Chemical structures of the 3S and 3R enantiomers of four α-amido trifluoromethylketones and racemic trifluoromethyl alcohols.
Chemical structures of the 3S and 3R enantiomers of four α-amido trifluoromethylketones and racemic trifluoromethyl alcohols.
Chemical structures of amino acid-derived hydroxamates synthesized by Walter et al. (1999).
Chemical structures of amino acid-derived hydroxamates synthesized by Walter et al. (1999).
Chemical structures of four derivatives of mercaptoacetic acid thiol ester.
Chemical structures of four derivatives of mercaptoacetic acid thiol ester.
Chemical structures of some of the thioesters and thiols developed by the Merck group.
Chemical structures of some of the thioesters and thiols developed by the Merck group.
General structure of thiols developed by M. Page and coworkers (1998). The chemical structures of two thiols synthesized at SmithKline Beecham are shown.
General structure of thiols developed by M. Page and coworkers (1998). The chemical structures of two thiols synthesized at SmithKline Beecham are shown.
Chemical structures of L-158,817, L-159,061, and L-159,906.
Chemical structures of L-158,817, L-159,061, and L-159,906.
Coordination environment of the zinc sites in the B. fragilis metallo-β-lactamase, showing the bridging water (Wat1) and the water coordinated to Zn2 (Wat2). Reprinted from S. D. B. Scrofani, J. Chung, J. J. A. Huntley, S. J. Benkovic, P. E. Wright, and H. J. Dyson, Biochemistry 38:14507–14514, 1999, with permission from the publisher.
Coordination environment of the zinc sites in the B. fragilis metallo-β-lactamase, showing the bridging water (Wat1) and the water coordinated to Zn2 (Wat2). Reprinted from S. D. B. Scrofani, J. Chung, J. J. A. Huntley, S. J. Benkovic, P. E. Wright, and H. J. Dyson, Biochemistry 38:14507–14514, 1999, with permission from the publisher.
X-ray crystal structure of L-159,061 bound in the active site of the B. fragilis metallo-β-lactamase. A view of the active site is shown. Reprinted from J. H. Toney, P. M. Fitzgerald, N. Grover-Sharma, et al., Chem. Biol. 5:185–196, 1998, with permission from the publisher.
X-ray crystal structure of L-159,061 bound in the active site of the B. fragilis metallo-β-lactamase. A view of the active site is shown. Reprinted from J. H. Toney, P. M. Fitzgerald, N. Grover-Sharma, et al., Chem. Biol. 5:185–196, 1998, with permission from the publisher.
Dates when β-lactam antibiotics and the combinations of a β-lactam antibiotic with a β-lactamase inhibitor were approved for use in the United States
Dates when β-lactam antibiotics and the combinations of a β-lactam antibiotic with a β-lactamase inhibitor were approved for use in the United States
Amino acid substitutions in the TEM ESBLs and inhibitor-resistant β-lactamases a
Amino acid substitutions in the TEM ESBLs and inhibitor-resistant β-lactamases a
Amino acid substitutions in the SHV ESBLs and IRT β-lactamases a
Amino acid substitutions in the SHV ESBLs and IRT β-lactamases a
Amino acid substitution in the OXA extended-spectrum β-lactamases a
Amino acid substitution in the OXA extended-spectrum β-lactamases a
Antibacterial activity of trinem derivatives and vancomycin a
Antibacterial activity of trinem derivatives and vancomycin a
Inhibition of representative serine β-lactamases by compounds 1a to 1d and 2 relative to tazobactam a
Inhibition of representative serine β-lactamases by compounds 1a to 1d and 2 relative to tazobactam a