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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 β-lactam bond cleavage by β-lactamases to selectively trigger antibacterial prodrugs into the bacterial periplasm. Indeed, multidrug-resistant Gram-negative pathogens commonly produce several β-lactamases that are able to inactivate β-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 β-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.