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Chapter 12 : Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases
Author:
Oreste A. Mascaretti1
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Affiliations:
1: Department of Organic Chemistry, Faculty of Biochemistry and Pharmacy, Universidad Nacional de Rosario, Rosario, Argentina
Content Type: Textbook
Publication Year:
2003
Category: Bacterial Pathogenesis
Book DOI:
10.1128/9781555817794
Chapter DOI:
10.1128/9781555817794.ch12
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Abstract:
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
Figures
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-1
Figure 12.1
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
10.1128/9781555817794/fig12-1_thmb.gif
10.1128/9781555817794/fig12-1.gif
Figure 12.1
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
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-2
Figure 12.2
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).
10.1128/9781555817794/fig12-2_thmb.gif
10.1128/9781555817794/fig12-2.gif
Figure 12.2
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).
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-3
Figure 12.3
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.
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10.1128/9781555817794/fig12-3.gif
Figure 12.3
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-4
Figure 12.4
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.
10.1128/9781555817794/fig12-4_thmb.gif
10.1128/9781555817794/fig12-4.gif
Figure 12.4
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-5
Figure 12.5
Chemical structure of the cephalosporin BMS-247243.
10.1128/9781555817794/fig12-5_thmb.gif
10.1128/9781555817794/fig12-5.gif
Figure 12.5
Chemical structure of the cephalosporin BMS-247243.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-6
Figure 12.6
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.
10.1128/9781555817794/fig12-6_thmb.gif
10.1128/9781555817794/fig12-6.gif
Figure 12.6
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-7
Figure 12.7
Chemical structure of SM-17466.
10.1128/9781555817794/fig12-7_thmb.gif
10.1128/9781555817794/fig12-7.gif
Figure 12.7
Chemical structure of SM-17466.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-8
Figure 12.8
Structure 1a is the general chemical structure of trinems. Structure 1b is the chemical structure of sanfetrinem and the ester sanfetrinem cilexetil.
10.1128/9781555817794/fig12-8_thmb.gif
10.1128/9781555817794/fig12-8.gif
Figure 12.8
Structure 1a is the general chemical structure of trinems. Structure 1b is the chemical structure of sanfetrinem and the ester sanfetrinem cilexetil.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-9
Figure 12.9
Chemical structures of novel trinems synthesized at Sankyo Laboratories.
10.1128/9781555817794/fig12-9_thmb.gif
10.1128/9781555817794/fig12-9.gif
Figure 12.9
Chemical structures of novel trinems synthesized at Sankyo Laboratories.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-10
Figure 12.10
Chemical structure of LB-10517.
10.1128/9781555817794/fig12-10_thmb.gif
10.1128/9781555817794/fig12-10.gif
Figure 12.10
Chemical structure of LB-10517.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-11
Figure 12.11
Chemical structure of BMS-180680.
10.1128/9781555817794/fig12-11_thmb.gif
10.1128/9781555817794/fig12-11.gif
Figure 12.11
Chemical structure of BMS-180680.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-12
Figure 12.12
Chemical structure of a rhodanine synthesized at Johnson Pharmaceutical.
10.1128/9781555817794/fig12-12_thmb.gif
10.1128/9781555817794/fig12-12.gif
Figure 12.12
Chemical structure of a rhodanine synthesized at Johnson Pharmaceutical.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-13
Figure 12.13
Chemical structures of 3-substituted 7-(alkylidene) cephalosporin sulfones and 6-alkylidene-2′β-substituted penam sulfones.
10.1128/9781555817794/fig12-13_thmb.gif
10.1128/9781555817794/fig12-13.gif
Figure 12.13
Chemical structures of 3-substituted 7-(alkylidene) cephalosporin sulfones and 6-alkylidene-2′β-substituted penam sulfones.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-14
Figure 12.14
Chemical structure of compound 1 synthesized by Bitha et al. at Wyeth-Ayerst.
10.1128/9781555817794/fig12-14_thmb.gif
10.1128/9781555817794/fig12-14.gif
Figure 12.14
Chemical structure of compound 1 synthesized by Bitha et al. at Wyeth-Ayerst.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-15
Figure 12.15
Chemical structures of the 3S and 3R enantiomers of four α-amido trifluoromethylketones and racemic trifluoromethyl alcohols.
10.1128/9781555817794/fig12-15_thmb.gif
10.1128/9781555817794/fig12-15.gif
Figure 12.15
Chemical structures of the 3S and 3R enantiomers of four α-amido trifluoromethylketones and racemic trifluoromethyl alcohols.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-16
Figure 12.16
Chemical structures of amino acid-derived hydroxamates synthesized by Walter et al. (1999).
10.1128/9781555817794/fig12-16_thmb.gif
10.1128/9781555817794/fig12-16.gif
Figure 12.16
Chemical structures of amino acid-derived hydroxamates synthesized by Walter et al. (1999).
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-17
Figure 12.17
Chemical structures of four derivatives of mercaptoacetic acid thiol ester.
10.1128/9781555817794/fig12-17_thmb.gif
10.1128/9781555817794/fig12-17.gif
Figure 12.17
Chemical structures of four derivatives of mercaptoacetic acid thiol ester.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-18
Figure 12.18
Chemical structures of some of the thioesters and thiols developed by the Merck group.
10.1128/9781555817794/fig12-18_thmb.gif
10.1128/9781555817794/fig12-18.gif
Figure 12.18
Chemical structures of some of the thioesters and thiols developed by the Merck group.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-19
Figure 12.19
General structure of thiols developed by M. Page and coworkers (1998). The chemical structures of two thiols synthesized at SmithKline Beecham are shown.
10.1128/9781555817794/fig12-19_thmb.gif
10.1128/9781555817794/fig12-19.gif
Figure 12.19
General structure of thiols developed by M. Page and coworkers (1998). The chemical structures of two thiols synthesized at SmithKline Beecham are shown.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-20
Figure 12.20
Chemical structures of L-158,817, L-159,061, and L-159,906.
10.1128/9781555817794/fig12-20_thmb.gif
10.1128/9781555817794/fig12-20.gif
Figure 12.20
Chemical structures of L-158,817, L-159,061, and L-159,906.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-21
Figure 12.21
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.
10.1128/9781555817794/fig12-21_thmb.gif
10.1128/9781555817794/fig12-21.gif
Figure 12.21
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.fig12-22
Figure 12.22
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.
10.1128/9781555817794/fig12-22_thmb.gif
10.1128/9781555817794/fig12-22.gif
Figure 12.22
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.
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
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Tables
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-1
Table 12.1
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
Table 12.1
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
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-2
Table 12.2
Amino acid substitutions in the TEM ESBLs and inhibitor-resistant β-lactamases a
Table 12.2
Amino acid substitutions in the TEM ESBLs and inhibitor-resistant β-lactamases a
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-3
Table 12.3
Amino acid substitutions in the SHV ESBLs and IRT β-lactamases a
Table 12.3
Amino acid substitutions in the SHV ESBLs and IRT β-lactamases a
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-4
Table 12.4
Amino acid substitution in the OXA extended-spectrum β-lactamases a
Table 12.4
Amino acid substitution in the OXA extended-spectrum β-lactamases a
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-5
Table 12.5
Antibacterial activity of trinem derivatives and vancomycin a
Table 12.5
Antibacterial activity of trinem derivatives and vancomycin a
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12
/content/10.1128/9781555817794.chap12.tab12-6
Table 12.6
Inhibition of representative serine β-lactamases by compounds 1a to 1d and 2 relative to tazobactam a
Table 12.6
Inhibition of representative serine β-lactamases by compounds 1a to 1d and 2 relative to tazobactam a
Citation:
Mascaretti O.
2003.
Bacterial Resistance to β-Lactam Antibiotics and β-Lactam Inhibitors of β-Lactamases,
p 171-198.
In
Bacteria versus Antibacterial Agents.
ASM Press, Washington, DC.
doi: 10.1128/9781555817794.ch12