Challenges in the Development of a Thiol-Based Broad-Spectrum Inhibitor for Metallo-β-Lactamases

Abstract

Pathogens, expressing metallo-β-lactamases (MBLs), become resistant against most β-lactam antibiotics. Besides the dragging search for new antibiotics, development of MBL inhibitors would be an alternative weapon against resistant bacterial pathogens. Inhibition of resistance enzymes could restore the antibacterial activity of β-lactams. Various approaches to MBL inhibitors are described; among others, the promising motif of a zinc coordinating thiol moiety is very popular. Nevertheless, since the first report of a thiol-based MBL inhibitor (thiomandelic acid) in 2001, no steps in development of thiol based MBL inhibitors were reported that go beyond clinical isolate testing. In this study, we report on the synthesis and biochemical characterization of thiol-based MBL inhibitors and highlight the challenges behind the development of thiol-based compounds, which exhibit good in vitro activity toward a broad spectrum of MBLs, selectivity against human off-targets, and reasonable activity against clinical isolates.

Structural and biochemical analysis of the metallo‐β‐lactamase L1 from emerging pathogen Stenotrophomonas maltophilia revealed the subtle but distinct di‐metal scaffold for catalytic activity

“…Dependent on L‐ or D‐ configuration of the proline moiety, the carboxyl group is facing a different side of the binding pocket and in the L1‐D‐captopril complex (2FU8), the carboxyl oxygen makes a hydrogen bond to OG of Ser223. The binding site of L1 (or other MLB) can accommodate various forms of a captopril molecule suggesting utilizable room to introduce derivatives for higher selectivity and affinity . The L1 structures are quite similar and all inter‐metal distances in the structures are around 3.7–3.8 Å.…”

“…The binding site of L1 (or other MLB) can accommodate various forms of a captopril molecule suggesting utilizable room to introduce derivatives for higher selectivity and affinity. 20,47 The L1 structures are quite similar and all inter-metal distances in the structures are around 3.7-3.8 Å.…”

Approaches for the discovery of metallo‐β‐lactamase inhibitors: A review

“…Similar strategy has been used to discover thiorphan, tiopronin, and dimercaprol (Figure .8–10), which have the ability to inhibit NDM‐1, VIM‐1, and IMP‐7. Recently, some thiol‐based MBL inhibitors have been reported (Arjomandi et al., ; Büttner et al., ; Liu, Jing et al., ), including a series of amino acid‐derived thiol inhibitors reported by Arjomandi, in which the most potent compound of L‐tyrosine showed competitive inhibition with a Ki of 86 nM (Figure .11) (Arjomandi et al., ).…”

Synthesis and enzyme-based evaluation of analogues L-tyrosine thiol carboxylic acid inhibitor of metallo-β-lactamase IMP-1

“…7 For instance, thiomandelic acid and 2-mercapto-5-phenylpentanoic acid were discovered as a broad-spectrum inhibitor for MBLs where Cd-NMR studies demonstrated that the sulphur atom of the compound intercalates the metal ions within the active site and displaces the bridging water molecule that is essential for the MBL hydrolase activity. Further potent thiol containing compound reported with good IC50 by B€ uttner et al 42 The other potent thiol carboxylic acid compounds, bisthiazolidines, reported by Gonz alez et al 43 with Ki values in a range of 7-19 mM against NDM-1. The co-crystallised enzyme/ inhibitors of these compounds demonstrated that the sulphur atom of the mercaptomethyl group is positioned nearly equidistant between the two zinc ions, displacing the bridging water/ hydroxide molecule that is proposed to be the attacking nucleophile, but with little impact on the Zn1 À Zn2 distance.…”