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Chapter 8 : Inhibition of Class A β-Lactamases
Authors:
Samy O. Meroueh1,
Jooyoung Cha2,
Shahriar Mobashery3
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Affiliations:
1: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
2: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
3: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556
Content Type: Monograph
Publication Year:
2007
Category: Bacterial Pathogenesis
Book DOI:
10.1128/9781555815615
Chapter DOI:
10.1128/9781555815615.ch8
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Inhibition of Class A β-Lactamases, Page 1 of 2
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Abstract:
The catalytic function of β-lactamases is the primary mechanism of bacterial resistance to β-lactam antibiotics (penicillins, cephalosporins, carbapenems). β-lactamases hydrolyze the β-lactam bond of these antibiotics, a structure modification that abrogates the antibacterial activity. β-lactams include tazobactam, a highly effective sulfone penam inhibitor, penicillanic acid sulfone sulbactam, 6-β-bromopenicillanic acid, and thienamycin. Clavulanate is a potent inhibitor of class A β-lactamases, which incidentally exhibits weak antimicrobial activity as well. A series of molecules-using sulfoxide and sulfone penams have been synthesized as starting points-with sulfhydryl and sulfide moieties at C-6; the goal of this exercise was to arrive at molecules that would simultaneously inhibit classes A and B of β-lactamases. The study also confirmed that the sulfone oxidation state of the penam thiazolidine resulted in greater inhibition. The success of BRL 42715 prompted additional efforts into compounds with a double bond at C-6, leading to the discovery of SYN-1012-with a methyl triazolyl moiety at C6 instead-and another more recent methylidene penem-with a bicyclic and heterocyclic moiety at C-6; both of these compounds show good activity against class A and C β-lactamases. Several routes have been taken towards the development of more effective inhibitors including the syntheses of variants of penam sulfones, penems, alkylidenes, monobactams, transition-state analogs, and the boronates.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
Figures
Inhibition of Class A β-Lactamases
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Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig01
Figure 8.1
Stereoview of the three-dimensional structure of TEM-1 β-lactamase shown in ribbon representation (Protein Data Bank [PDB] code 1BTL). (B) Stereoview of a close-up of the active site of TEM-1 showing Glu-166 (9 o’clock), Lys-73 (11 o’clock), Ser-130 (12 o’clock), Lys-234 (2 o’clock), and Ser-70 (center). The enzyme is shown in ribbon representation, and residues are shown in capped-sticks representation. The conserved water molecule is shown as a sphere. (C) Stereoview of the acyl enzyme complex of a deacylation-deficient TEM β-lactamase in complex with benzylpenicillin (PDB code 1TEM). The enzyme is rendered in ribbon representation, and residues Glu-166 (9 o’clock), Lys-73 (12 o’clock), Ser-130 (1 o’clock), and Lys-234 (3 o’clock) are shown in capped sticks. An arrow is used to point to the C-6 side chain of the bound benzylpenicillin. The hydrolytic water is shown as a sphere.
10.1128/9781555815615/f0102-01_thmb.gif
10.1128/9781555815615/f0102-01.gif
Figure 8.1
Stereoview of the three-dimensional structure of TEM-1 β-lactamase shown in ribbon representation (Protein Data Bank [PDB] code 1BTL). (B) Stereoview of a close-up of the active site of TEM-1 showing Glu-166 (9 o’clock), Lys-73 (11 o’clock), Ser-130 (12 o’clock), Lys-234 (2 o’clock), and Ser-70 (center). The enzyme is shown in ribbon representation, and residues are shown in capped-sticks representation. The conserved water molecule is shown as a sphere. (C) Stereoview of the acyl enzyme complex of a deacylation-deficient TEM β-lactamase in complex with benzylpenicillin (PDB code 1TEM). The enzyme is rendered in ribbon representation, and residues Glu-166 (9 o’clock), Lys-73 (12 o’clock), Ser-130 (1 o’clock), and Lys-234 (3 o’clock) are shown in capped sticks. An arrow is used to point to the C-6 side chain of the bound benzylpenicillin. The hydrolytic water is shown as a sphere.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig02
Figure 8.2
Chemical structures of some inhibitors of class A β-lactamases.
10.1128/9781555815615/f0103-01_thmb.gif
10.1128/9781555815615/f0103-01.gif
Figure 8.2
Chemical structures of some inhibitors of class A β-lactamases.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig03
Figure 8.3
Chemistry of inhibition of class A β-lactamases by clavulanate.
10.1128/9781555815615/f0104-01_thmb.gif
10.1128/9781555815615/f0104-01.gif
Figure 8.3
Chemistry of inhibition of class A β-lactamases by clavulanate.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig04
Figure 8.4
Chemistry of inhibition of class A β-lactamases by tazobactam.
10.1128/9781555815615/f0105-01_thmb.gif
10.1128/9781555815615/f0105-01.gif
Figure 8.4
Chemistry of inhibition of class A β-lactamases by tazobactam.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig05
Figure 8.5
(A) Stereoview of the active site of SHV-1 showing intermediates 16 and 22 (Protein Data Bank [PDB] code 1G56). The bottom arrows point to 16, while the top arrow points to 22. The protein is rendered in ribbon, while Ser-70 (covalently bound to inhibitor; center), Glu-166 (10 o’clock), Lys-73 (12 o’clock), Ser-130 (covalently bound to inhibitor; 1 o’clock), and Lys-234 (3 o’clock) are shown in capped-sticks representation. (B) Intermediate 18 shown in the active site of SHV-2. The arrows point to the bound inhibitor that is attached to Ser-70 (center). Lys-73 (12 o’clock), Ser-130 (1 o’clock), and Lys-234 (2 o’clock) are shown in capped-sticks representation (PDB code 1RCJ).
10.1128/9781555815615/f0105-02_thmb.gif
10.1128/9781555815615/f0105-02.gif
Figure 8.5
(A) Stereoview of the active site of SHV-1 showing intermediates 16 and 22 (Protein Data Bank [PDB] code 1G56). The bottom arrows point to 16, while the top arrow points to 22. The protein is rendered in ribbon, while Ser-70 (covalently bound to inhibitor; center), Glu-166 (10 o’clock), Lys-73 (12 o’clock), Ser-130 (covalently bound to inhibitor; 1 o’clock), and Lys-234 (3 o’clock) are shown in capped-sticks representation. (B) Intermediate 18 shown in the active site of SHV-2. The arrows point to the bound inhibitor that is attached to Ser-70 (center). Lys-73 (12 o’clock), Ser-130 (1 o’clock), and Lys-234 (2 o’clock) are shown in capped-sticks representation (PDB code 1RCJ).
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig06
Figure 8.6
Chemical structures of penam sulfone (
23
) and derivatives.
10.1128/9781555815615/f0106-01_thmb.gif
10.1128/9781555815615/f0106-01.gif
Figure 8.6
Chemical structures of penam sulfone ( 23 ) and derivatives.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig07
Figure 8.7
Synthetic inhibitors based on the structure of 6-(nitrileoxidomethyl)penam sulfone active in inhibition of classes A, B, and C of β-lactamases.
10.1128/9781555815615/f0106-02_thmb.gif
10.1128/9781555815615/f0106-02.gif
Figure 8.7
Synthetic inhibitors based on the structure of 6-(nitrileoxidomethyl)penam sulfone active in inhibition of classes A, B, and C of β-lactamases.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig08
Figure 8.8
Chemical structures of additional inhibitors based on the penam sulfone nucleus.
10.1128/9781555815615/f0106-03_thmb.gif
10.1128/9781555815615/f0106-03.gif
Figure 8.8
Chemical structures of additional inhibitors based on the penam sulfone nucleus.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig09
Figure 8.9
Chemical structures of representative carbapenems.
10.1128/9781555815615/f0107-01_thmb.gif
10.1128/9781555815615/f0107-01.gif
Figure 8.9
Chemical structures of representative carbapenems.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig10
Figure 8.10
Inhibitory mechanism of β-lactamase by carbapenems.
10.1128/9781555815615/f0107-02_thmb.gif
10.1128/9781555815615/f0107-02.gif
Figure 8.10
Inhibitory mechanism of β-lactamase by carbapenems.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig11
Figure 8.11
Synthetic carbapenem derivatives that serve as inhibitors of classes A and C of β-lactamases.
10.1128/9781555815615/f0108-01_thmb.gif
10.1128/9781555815615/f0108-01.gif
Figure 8.11
Synthetic carbapenem derivatives that serve as inhibitors of classes A and C of β-lactamases.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig12
Figure 8.12
Inhibitory mechanism of penem BRL 42715 (
47
).
10.1128/9781555815615/f0109-01_thmb.gif
10.1128/9781555815615/f0109-01.gif
Figure 8.12
Inhibitory mechanism of penem BRL 42715 ( 47 ).
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig13
Figure 8.13
Stereoview of intermediate (
49
) bound to the active site of SHV-1 (Protein Data Bank [PDB] code 1ONH). The enzyme is shown in ribbon representation, while the bound ligand and active-site residues Glu-166 (9 o’clock), Lys-73 (11 o’clock), Ser-130 (12 o’clock), Lys-234 (2 o’clock), and Arg-244 (5 o’clock) are shown in capped-sticks representation. The arrows point to the thiazepine intermediate that is bound to Ser-70.
10.1128/9781555815615/f0109-02_thmb.gif
10.1128/9781555815615/f0109-02.gif
Figure 8.13
Stereoview of intermediate ( 49 ) bound to the active site of SHV-1 (Protein Data Bank [PDB] code 1ONH). The enzyme is shown in ribbon representation, while the bound ligand and active-site residues Glu-166 (9 o’clock), Lys-73 (11 o’clock), Ser-130 (12 o’clock), Lys-234 (2 o’clock), and Arg-244 (5 o’clock) are shown in capped-sticks representation. The arrows point to the thiazepine intermediate that is bound to Ser-70.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig14
Figure 8.14
Inhibitory mechanism of monobactam derivative 53 against class A β-lactamases.
10.1128/9781555815615/f0110-01_thmb.gif
10.1128/9781555815615/f0110-01.gif
Figure 8.14
Inhibitory mechanism of monobactam derivative 53 against class A β-lactamases.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig15
Figure 8.15
Schematic of phosphonate interactions with nucleophiles.
10.1128/9781555815615/f0110-02_thmb.gif
10.1128/9781555815615/f0110-02.gif
Figure 8.15
Schematic of phosphonate interactions with nucleophiles.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig16
Figure 8.16
Chemical structure of synthetic phosphonate-based transition-state analog inhibitors.
10.1128/9781555815615/f0110-03_thmb.gif
10.1128/9781555815615/f0110-03.gif
Figure 8.16
Chemical structure of synthetic phosphonate-based transition-state analog inhibitors.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig17
Figure 8.17
Chemical structure of cyclic phosphonate-based transition-state analog inhibitors.
10.1128/9781555815615/f0111-01_thmb.gif
10.1128/9781555815615/f0111-01.gif
Figure 8.17
Chemical structure of cyclic phosphonate-based transition-state analog inhibitors.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig18
Figure 8.18
Chemical structure of boronate transition-state analog inhibitors.
10.1128/9781555815615/f0111-02_thmb.gif
10.1128/9781555815615/f0111-02.gif
Figure 8.18
Chemical structure of boronate transition-state analog inhibitors.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig19
Figure 8.19
Chemical structure of a potent boronate inhibitor.
10.1128/9781555815615/f0111-03_thmb.gif
10.1128/9781555815615/f0111-03.gif
Figure 8.19
Chemical structure of a potent boronate inhibitor.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
/content/10.1128/9781555815615.ch08.ch08fig20
Figure 8.20
Cephalosporin-based inhibitors and the inhibitory mechanism against class C β-lactamases.
10.1128/9781555815615/f0111-04_thmb.gif
10.1128/9781555815615/f0111-04.gif
Figure 8.20
Cephalosporin-based inhibitors and the inhibitory mechanism against class C β-lactamases.
Citation:
Meroueh S, Cha J, Mobashery S.
2007.
Inhibition of Class A β-Lactamases,
p 101-114.
In
Bonomo R, Tolmasky M (ed),
Enzyme-Mediated Resistance to Antibiotics.
ASM Press, Washington, DC.
doi: 10.1128/9781555815615.ch8
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