Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.Peer reviewe

Enolātu enantioselektīvā protonēšana

Promocijas darbs veltīts enantiomēri tīru 1,3–diamīnu sintēzei un pielietojumam litija enolātu enantioselektīvās protonēšanas reakcijā. Hirālo 1,3- diamīnu iegūšanai izstrādāta stereoselektīva sintēzes metode, kura balstās uz terc- butānsulfinilimīnu diastereoselektīvu reducēšanu. Noskaidrotas likumsakarības starp terc-butānsulfinilimīnu uzbūvi (E/Z un M/P ģeometriju) un reducēšanas reakcijā jaunradītā asimetriskā centra konfigurāciju. terc-Butānsulfinilimīnu E/Z un M/P konfigurācijas pētītas gan kristāliskajā formā (izmantojot rentgenstruktūras analīzes metodi), gan arī THF–d8 šķīdumā (lietojot KMR metodes). Noteiktas imīnu E/Z izomerizācijas un M/P atropizomerizācijas ātruma konstantes un aprēķinātas izomerizācijas Gibsa brīvās aktivācijas enerģijas. Sintezētie enantiomēri tīrie 1,3-diamīni izmantoti kā hirāli protonu avoti naproksēnamīda litija enolāta enantioselektīvas protonēšanas reakcijā. Pētītas likumsakarības starp 1,3-diamīnu telpiskām prasībām un protona pārneses enantioselektivitāti. Noskaidrots hirālā protonu avota pamata struktūrelements, kurš nodrošina protona donora spēju atšķirt planārā enolāta enantiotopās puses

Asymmetric Synthesis of 1,3-Diamines.II: Diastereoselective Reduction of Atropisomeric N-tert-Butanesulfinylketimines"

Diastereoselective reduction of atropisomeric N-tert-butanesulfinylketimine

Imitation of β-lactam binding enables broad-spectrum metallo-β-lactamase inhibitors

Carbapenems are vital antibiotics, but their efficacy is increasingly compromised by metallo-beta-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 beta-lactamase stable beta-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.Peer reviewe