Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases

Abstract

Although commercialized inhibitors of active site serine beta-lactamases are currently used in coadministration with antibiotic therapy, no clinically useful inhibitors of metallo-beta-lactamases (MBLs) have yet been discovered. In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of 1a, behaved as competitive inhibitors for the three subclasses. Apart from 13 and 21, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (K(i) < 15 muM). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor. The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn(2+) ion, respectively. Molecular modeling studies of the interactions between compounds 10a and 18 and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.

Structural Insights into the Subclass B3 Metallo-β-Lactamase SMB-1 and the Mode of Inhibition by the Common Metallo-β-Lactamase Inhibitor Mercaptoacetate

“…Not only the thiolate group, but also the O2 atom of the carboxylate group in MCR is bound to Zn2 (2.6 Å), resulting in formation of a stable fivemembered chelate ring (Fig. 3B); in most of the structures of MBLs complexed with compounds including a thiolate group determined thus far, only the thiolate group of the compound was coordinated to zinc ions (47)(48)(49)(50).…”

Crystal Structure of the Mobile Metallo-β-Lactamase AIM-1 from Pseudomonas aeruginosa: Insights into Antibiotic Binding and the Role of Gln157

“…In addition, MBLs have been discovered in a range of environmental and clinically innocuous bacteria (2, 59, 61). The hydrolytic spectrum of MBLs includes all ␤-lactams, with the exception of monobactams (aztreonam) (59), and they are not inhibited by serine ␤-lactamase inhibitors, such as clavulanic acid, tazobactam, and sulbactam, in clinical use (19,33,45).MBLs are divided into three subclasses (B1, B2, and B3) on the basis of sequence similarity and structural features (2). Prior to the identification of AIM-1 (Adelaide IMipenmase 1) in P. aeruginosa (63) and the recently published SMB-1 (57), other acquired or mobile MBLs (IMPs, VIMs, NDMs, SPM, GIM, SIM, DIM, TMB-1, and KHM-1) (58) were almost exclusively confined to the B1 subclass.…”

Optimisation of lead inhibitors of the imipenemase 1 (IMP-1) metallo-β-lactamase enzyme

“…63 In the CphA-47a complex, the thiolate functional group is responsible for binding to the Zn 2+ ion (Figure 1.31a). 63 Molecular docking suggested that the two bulky isopropyl groups of 47a may have blocked the phosphonate oxygen of the inhibitor from binding to the Zn 2+ ion. 63 On the other hand, inhibitor 51 binds to the Zn 2+ ion via two of its phosphonate oxygen atoms (O11 and O12) (Figure 1.31b).…”

“…63 Molecular docking suggested that the two bulky isopropyl groups of 47a may have blocked the phosphonate oxygen of the inhibitor from binding to the Zn 2+ ion. 63 On the other hand, inhibitor 51 binds to the Zn 2+ ion via two of its phosphonate oxygen atoms (O11 and O12) (Figure 1.31b). 63 The thiol group of inhibitor 51 instead, interacts with a water molecule (W347, 3.06 Å) and the backbone nitrogen of Asn233 (3.45 Å), which is part of the Gly232-Asn233 loop that closes upon inhibitor binding.…”

“…63 The thiol group of inhibitor 51 instead, interacts with a water molecule (W347, 3.06 Å) and the backbone nitrogen of Asn233 (3.45 Å), which is part of the Gly232-Asn233 loop that closes upon inhibitor binding. 63 In addition, O12 of inhibitor 51 also has an interaction with Lys224, via a hydrogen bond (2.72Å). …”