Abstract
β-Lactam antibiotics are the most widely prescribed antibacterial drugs due to their low toxicity and broad spectrum. Their action is counteracted by different resistance mechanisms developed by bacteria. Among them, the most common strategy is the expression of β-lactamases, enzymes that hydrolyze the amide bond present in all β-lactam compounds. There are several inhibitors against serine-β-lactamases (SBLs). Metallo-β-lactamases (MBLs) are Zn(II)-dependent enzymes able to hydrolyze most β-lactam antibiotics, and no clinically useful inhibitors against them have yet been approved. Despite their large structural diversity, MBLs have a common catalytic mechanism with similar reaction species. Here, we describe a number of MBL inhibitors that mimic different species formed during the hydrolysis process: substrate, transition state, intermediate, or product. Recent advances in the development of boron-based and thiol-based inhibitors are discussed in the light of the mechanism of MBLs. We also discuss the use of chelators as a possible strategy, since Zn(II) ions are essential for substrate binding and catalysis.
Highlights
Antibiotic resistance has led to a global health crisis, as resistant infectious bacteria are becoming more widespread every day all over the world
These events are exacerbated by the misuse and abusive use of antibiotics that push the limits of bacterial resistance [6]
Combinations of these compounds with different penicillins and cephalosporins are used to treat infections caused by bacteria expressing many class A several inhibitors against serine-β-lactamases (SBLs) [8,28,108]. These drugs cannot inhibit class B, C, and D β-lactamases, nor class A carbapenemases such as KPC. Their mechanism of action is based on the reaction mechanism of SBLs, being susceptible to hydrolysis by the catalytic Ser residue
Summary
Antibiotic resistance has led to a global health crisis, as resistant infectious bacteria are becoming more widespread every day all over the world. Β-Lactam antibiotics are the most frequently prescribed and best-selling antimicrobial drugs (Figure 1) [7,8] Their success is due to their broad-spectrum of activity and their favorable safety profile. The mThoesrtewairdeessepvreeraadl mreescishtaannicsemms ebcyhwanhiiscmh b(baocttehriian bGercaomm-enreegsaitsitvaentatnodβG-lraacmtam-poasnittiivbeiobtiacsct[e2r6ia].) Tishtehme eoxstprweisdsieosnproefadhyrdesriosltyatnicceenmzeycmhaensisnmam(beodthβ-ilnacGtarmamas-neseg[a2t7i,v2e8]a.nTdhGesreamen-pzoysmiteivsecabtaacltyezreiat)hies the expression of hydrolytic enzymes named β-lactamases [27,28] These enzymes catalyze the Biomolecules 2020, 10, 854 cleavage of the amide bond of β-lactams (Figure 1), rendering the antibiotics ineffective against their targets [26]. Class B are Zn(II)-dependent hydrolases (Figure 2), generally known as metallo-β-lactamases (MBLs) [31] These enzymes do not share any structural, mechanistic or sequence homology with SBLs or PBPs, indicating an independent evolutionary origin [34,35,36]. ZZnn((IIII)) iioonnss aarree sshhoowwnn aass ggrreeyy sspphheerreessaannddwwaatetre/rO/OHHmmoloelceucluelseassarsedresdphsperheesr.eZs.nZ(InI)(IiIn)teinratecrtiaocntisoanrseasrheoswhnowasndaasshdeadshliendeslianneds manedtalmliegtaanl dlisgaarnedsshoarwensihnocwonlori.nRceosildoru.eRs easreidnuuems baererednuamccboerrdeidngatcocothrdeisntgantdoartdheMsBtaLnnduamrdbeMriBnLg sncuhmembeer.inFgorstchheemB2e.eFnozrymthee SBf2he-In, zthyemaecStifvhe-Im, tohneoa-cZtniv(eII)mfoornmo-Zisns(hIIo)wfonr.m is shown
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