Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases

Addressing antibacterial resistance is a major concern of the modern world. The development of new approaches to meet this deadly threat is a critical priority. In this article, we investigate a new approach to negate bacterial resistance: exploit the ss-lactam bond cleavage by ss-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrug-resistant Gram-negative pathogens commonly produce several ss-lactamases that are able to inactivate ss-lactam antibiotics, our most reliable and widely used therapeutic option. The chemical structure of these prodrugs is based on a monobactam promoiety, covalently attached to the active antibacterial substance, zidovudine (AZT). We describe the synthesis of 10 prodrug analogues (5a-h) in four to nine steps and their biological activity. Selective enzymatic activation by a panel of ss-lactamases is demonstrated, and subsequent structure-activity relationships are discussed. The best compounds are further evaluated for their activity on both laboratory strains and clinical isolates, preliminary stability, and toxicity.