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Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®

2014; Elsevier BV; Volume: 24; Issue: 3 Linguagem: Inglês

10.1016/j.bmcl.2013.12.101

1464-3405

Timothy A. Blizzard, Helen Chen, Seongkon Kim, Jane Y. Wu, Rena Bodner, Candido Gude, Jason E. Imbriglio, Katherine Young, Young-Whan Park, Aimie M. Ogawa, Susan L. Raghoobar, Nichelle Hairston, Ronald E. Painter, Doug Wisniewski, Giovanna Scapin, Paula M.D. Fitzgerald, Nandini Sharma, Jun Lü, Sookhee Ha, Jeff Hermes, Milton L. Hammond,

Antibiotic Use and Resistance

β-Lactamase inhibitors with a bicyclic urea core and a variety of heterocyclic side chains were prepared and evaluated as potential partners for combination with imipenem to overcome class A and C β-lactamase mediated antibiotic resistance. The piperidine analog 3 (MK-7655) inhibited both class A and C β-lactamases in vitro. It effectively restored imipenem’s activity against imipenem-resistant Pseudomonas and Klebsiella strains at clinically achievable concentrations. A combination of MK-7655 and Primaxin® is currently in phase II clinical trials for the treatment of Gram-negative bacterial infections.