Zidovudine-β-Lactam Pronucleoside Strategy for Selective Delivery into Gram-Negative Bacteria Triggered by β-Lactamases
Résumé
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 βlactam bond cleavage by β-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrugresistant Gram-negative pathogens commonly produce several β-lactamases able to inactivate βlactam antibiotics, our most reliable and widely used therapeutic option. The chemical structure of those prodrugs is based on a monobactam promoiety, covalently attached to the active antibacterial substance, the zidovudine (AZT). We describe the synthesis of 10 prodrug analogs (5a-h) in 4-9 steps and their biological activity. Selective enzymatic activation by a panel of β-lactamases is demonstrated and subsequent structure-activity relationships (SARs) are discussed. The best compounds are further evaluated for their activity on both laboratory strains and clinical isolates, preliminary stability, and toxicity.
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