Institut des Biomolécules Max Mousseron, Univ Montpellier, CNRS, ENSCM, 34293 Montpellier, France.
Dipartimento di Biotecnologie Mediche, Università di Siena, I-53100 Siena, Italy.
ACS Infect Dis. 2023 Aug 11;9(8):1546-1557. doi: 10.1021/acsinfecdis.3c00110. Epub 2023 Jul 13.
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 () 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.
解决抗菌药物耐药性是当今世界面临的主要问题之一。开发新方法来应对这一致命威胁是当务之急。本文研究了一种克服细菌耐药性的新方法：利用β-内酰胺酶对β-内酰胺键的裂解作用，将选择性地将抗菌前药触发到细菌周质中。事实上，常见的多药耐药革兰氏阴性病原体通常会产生几种能够使β-内酰胺抗生素失活的β-内酰胺酶，β-内酰胺抗生素是我们最可靠和广泛使用的治疗选择。这些前药的化学结构基于单环酰胺促进剂，与活性抗菌物质齐多夫定（AZT）共价连接。我们描述了 10 种前药类似物（）的合成，总步骤数为四到九步，并研究了它们的生物学活性。通过一系列β-内酰胺酶的选择性酶促激活来证明，随后讨论了构效关系。对最佳化合物进行了进一步的实验室菌株和临床分离株活性、初步稳定性和毒性评估。
