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Chapter 8 : Inhibition of Class A β-Lactamases

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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 C 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

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beta-Lactam Antibiotics
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Figures

Image of Figure 8.1
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
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Image of Figure 8.2
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
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Image of Figure 8.3
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
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Image of Figure 8.4
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
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Image of Figure 8.5
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
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Image of Figure 8.6
Figure 8.6

Chemical structures of penam sulfone ( ) 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
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Image of Figure 8.7
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
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Image of Figure 8.8
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
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Image of Figure 8.9
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
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Image of Figure 8.10
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
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Image of Figure 8.11
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
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Image of Figure 8.12
Figure 8.12

Inhibitory mechanism of penem BRL 42715 ( ).

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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Image of Figure 8.13
Figure 8.13

Stereoview of intermediate ( ) 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
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Image of Figure 8.14
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
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Image of Figure 8.15
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
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Image of Figure 8.16
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
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Image of Figure 8.17
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
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Image of Figure 8.18
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
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Image of Figure 8.19
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
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Image of Figure 8.20
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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