MBLIs · New Approaches to Metallo-β-Lactamase Inhibitors

New Approaches to Metallo-β-Lactamase Inhibitors

The increasing problem of antibiotic resistance is a major global public health concern in Europe. The β-lactam antibiotics (BLAs) remain the most important antibiotics representing >60% of small molecules used for antibacterial therapy in clinical use. β-Lactam antibiotics contain the β-lactam ring which is critical for their mechanism of action which involves inhibition of penicillin-binding proteins (PBPs) that are essential for bacterial cell wall biosynthesis. BLA efficacy is declining due to resistance mechanisms including by the widespread occurrence of β-lactamases, which catalyse the hydrolysis of the β-lactam ring to give inert β-amino acids. There are two classes of β-lactamases (based on their mechanism of action): (a) the serine β-lactamases (SBLs; subdivided into class A-penicillinases, class C-cephalosporinases, and class D-oxacillinases) which employ a nucleophilic serine residue in catalysis, and (b) the metallo-β-lactamases (MBLs; class B) which require one or two zinc ions to activate a “hydrolytic” water molecule. The MBLs were long-considered as of little clinical relevance; however, they now present a serious global threat to the use of almost all BLAs (including carbapenems; “last resort” antibiotics) - with the only exception being Aztreonam – rendering the development of MBL inhibitors (MBLIs) important. Due to the variations in MBL structures, a major challenge in MBL inhibition is the development of compounds with the breadth of selectivity necessary for clinical use. This work aimed at the synthesis of broad-spectrum MBL inhibitors active against a panel of clinically representative MBLs, whilst maintaining selectivity against human MBL-fold enzymes which have related active sites, and some are crucially involved in DNA-repair (SNM1A and SNM1B), and other human metallo-enzymes. To date there are no clinically useful MBL inhibitors, in part due to selectivity issues. The work employed organic synthesis and was supported by dynamic combinatorial chemistry (DCC), MBL assay screening, biological NMR, structural biology, and medicinal chemistry. To address to problem of MBL resistance mechanism, novel synthetic methods were developed and led to the synthesis of a wide range of organic families including rhodanine derived enethiols, α-sulfanyl phosphonic acids, α-amino- phosphonic and -boronic acids as ‘transition state analogue’ based inhibitors, and indole carboxylates. The combined results revealed that low molecular weight active site Zn(II) chelating compounds can inhibit a range of clinically relevant MBLs. An important outcome of the work is the dual inhibitory activity of some organic families for both SBLs and MBLs, as well as the inhibition of PBPs, thus representing a promising line not only for the protection of β-lactam antibiotics from both MBLs and/or SBLs, but also for direct inhibition of PBPs.

Data: CORDIS, © European Union