Brem J, Panduwawala T, Hansen JU, Hewitt J, Liepins E, Donets P, Espina L, Farley AJM, Shubin K, Campillos GG, Kiuru P, Shishodia S, Krahn D, Leśniak RK, Schmidt Adrian J, Calvopiña K, Turrientes MC, Kavanagh ME, Lubriks D, Hinchliffe P, Langley GW, Aboklaish AF, Eneroth A, Backlund M, Baran AG, Nielsen EI, Speake M, Kuka J, Robinson J, Grinberga S, Robinson L, McDonough MA, Rydzik AM, Leissing TM, Jimenez-Castellanos JC, Avison MB, Da Silva Pinto S, Pannifer AD, Martjuga M, Widlake E, Priede M, Hopkins Navratilova I, Gniadkowski M, Belfrage AK, Brandt P, Yli-Kauhaluoma J, Bacque E, Page MGP, Björkling F, Tyrrell JM, Spencer J, Lang PA, Baranczewski P, Cantón R, McElroy SP, Jones PS, Baquero F, Suna E, Morrison A, Walsh TR, Schofield CJ
Nat Chem 14 (1) 15-24 [2022-01-00; online 2021-12-13]
Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-β-lactamases (MBLs). Here we report the discovery and optimization of potent broad-spectrum MBL inhibitors. A high-throughput screen for NDM-1 inhibitors identified indole-2-carboxylates (InCs) as potential β-lactamase stable β-lactam mimics. Subsequent structure-activity relationship studies revealed InCs as a new class of potent MBL inhibitor, active against all MBL classes of major clinical relevance. Crystallographic studies revealed a binding mode of the InCs to MBLs that, in some regards, mimics that predicted for intact carbapenems, including with respect to maintenance of the Zn(II)-bound hydroxyl, and in other regards mimics binding observed in MBL-carbapenem product complexes. InCs restore carbapenem activity against multiple drug-resistant Gram-negative bacteria and have a low frequency of resistance. InCs also have a good in vivo safety profile, and when combined with meropenem show a strong in vivo efficacy in peritonitis and thigh mouse infection models.
Drug Discovery and Development (DDD) [Service]