1. Discovery of MK-7655, a β-lactamase inhibitor for combination with Primaxin®
- Author
-
Timothy A. Blizzard, Nichelle Hairston, Jason E. Imbriglio, Young-Whan Park, Douglas Wisniewski, Paula M.D. Fitzgerald, Sookhee Ha, Nandini Sharma, Katherine Young, Jane Y. Wu, Giovanna Scapin, Aimie Ogawa, Susan L. Raghoobar, Jeff Hermes, Seongkon Kim, Ronald E. Painter, Rena Bodner, Jun Lu, Candido Gude, Helen Chen, and Milton L. Hammond
- Subjects
Imipenem ,Klebsiella ,medicine.drug_class ,Clinical Biochemistry ,Antibiotics ,Cilastatin, Imipenem Drug Combination ,Pharmaceutical Science ,Microbial Sensitivity Tests ,Crystallography, X-Ray ,Models, Biological ,Biochemistry ,Microbiology ,Inhibitory Concentration 50 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Pseudomonas ,Drug Resistance, Bacterial ,Drug Discovery ,medicine ,Enzyme Inhibitors ,Molecular Biology ,Vaborbactam ,Bicyclic molecule ,biology ,Chemistry ,Organic Chemistry ,biology.organism_classification ,In vitro ,Drug Combinations ,Cilastatin ,Molecular Medicine ,Piperidine ,beta-Lactamase Inhibitors ,Azabicyclo Compounds ,medicine.drug - Abstract
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.
- Published
- 2014