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Mandal, Mihirbaran; Xiao, Li; Pan, Weidong; Scapin, Giovanna; Li, Guoqing; Tang, Haiqun; Yang, Shu-Wei; Pan, Jianping; Root, Yuriko; de Jesus, Reynalda Keh; Yang, Christine; Prosise, Winnie; Dayananth, Priya; Mirza, Asra; Therien, Alex G.; Young, Katherine; Flattery, Amy; Garlisi, Charles; Zhang, Rumin; Chu, Donald; Sheth, Payal; Chu, Inhou; Wu, Jin; Markgraf, Carrie; Kim, Hai-Young; Painter, Ronald; Mayhood, Todd W.; DiNunzio, Edward; Wyss, Daniel F.; Buevich, Alexei V.; Fischmann, Thierry; Pasternak, Alexander; Dong, Shuzhi; Hicks, Jacqueline D.; Villafania, Artjohn; Liang, Lianzhu; Murgolo, Nicholas; Black, Todd; Hagmann, William K.; Tata, Jim; Parmee, Emma R.; Weber, Ann E.; Su, Jing; Tang, Haifeng
Journal of medicinal chemistry, 12/2022, Volume: 65, Issue: 24Journal Article
With the emergence and rapid spreading of NDM-1 and existence of clinically relevant VIM-1 and IMP-1, discovery of pan inhibitors targeting metallo-beta-lactamases (MBLs) became critical in our battle against bacterial infection. Concurrent with our fragment and high-throughput screenings, we performed a knowledge-based search of known metallo-beta-lactamase inhibitors (MBLIs) to identify starting points for early engagement of medicinal chemistry. A class of compounds exemplified by 11, discovered earlier as B. fragilis metallo-beta-lactamase inhibitors, was selected for in silico virtual screening. From these efforts, compound 12 was identified with activity against NDM-1 only. Initial exploration on metal binding design followed by structure-guided optimization led to the discovery of a series of compounds represented by 23 with a pan MBL inhibition profile. In in vivo studies, compound 23 in combination with imipenem (IPM) robustly lowered the bacterial burden in a murine infection model and became the lead for the invention of MBLI clinical candidates.
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