Structure activity relationship (SAR) driven design and discovery of WCK 5107 (Zidebactam): novel β-lactam enhancer, potent against multidrug-resistant gram-negative pathogens

Extended-spectrum beta-lactamases (ESBL) are the enzymes responsible for producing multidrug-resistant (MDR) bacterial strains, making currently available β-lactam drugs ineffective against such bacterial infections. Avibactam and relebactam are the two non-β-lactam inhibitors approved in combination with other antibiotics for clinical use and originated from the diazabicyclooctane (DBO) series. However with time, ESBL strains produce a high degree of resistance, causing such drug combinations to be ineffectual. Under our program to explore an advanced candidate effective against ESBL-producing pathogens, we have successfully developed a novel series of compounds bearing hydrazide function with a dual mode of action involving enzyme inhibition and better penicillin-binding protein (PBP) affinity. The selectivity of these molecules to bind with PBP2 provided an opportunity to combine it with β-lactam drugs having another PBP affinity and binding properties. Synergistic PBP binding effect favored positively for the development of the combination product with various β-lactam drugs. This new generation DBO analogs are termed as enhancers because it enhances the potency of partner drugs rather than restoring initial activity. Most of the compounds from novel hydrazide series are self-active, having reasonable minimum inhibitory concentration (MIC) values against Escherichia Coli , Klebsiella pneumoniae , Pseudomonas aeruginosa and Acinetobacter baumannii . In preclinical and clinical studies, these new chemical entities (NCEs) in combination with the β-lactam drug exhibited potency against a panel of gram-negative pathogens. WCK 5107 (Zidebactam) and WCK 5153 are the two potent β-lactam enhancers that emerged through this development. Notably, the cefepime combination of zidebactam (WCK 5222) received qualified infectious disease product (QIDP) status, completed global phase I clinical trial, and is currently in the global phase III stage.