Inactivating Inhibitors of Mycobacterium tuberculosis beta-lactamase BlaC

Washington State University, Pullman WA

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Abstract

? DESCRIPTION (provided by applicant): The intrinsic resistance of Mtb to ß-lactam antibiotics has limited the use of ß-lactam antibiotics as therapeutic agents to treat Mtb. Our long-term goal is to develop therapeutic and imaging agents for the early detection and treatment of Mtb infection. The overall objective of this application is to prove the concept that phosphonyl compounds can irreversibly phosphonylate and consequently inactivate serine ß-lactamases, specifically BlaC. The central hypothesis of this application is that serine ß-lactamases can be irreversibly inactivated by phosphonyl compounds. We will test our hypothesis and accomplish the objective of this application by pursuing the following two aims: (1) Develop acyclic phosphonamidate monoesters as putative serine ß- lactamase warheads (2) Develop cyclic phosphonyl compounds to serve as ß-lactam mimics. The rationale for undertaking the proposed work is that it will establish the feasibility of irreversibly modifiying ß-lactamase wit phosphonyl group. The expected outcome of the proposed work is that enabling technology will be developed for establishing a new antibiotic scaffold for Mtb and a platform for developing an imaging agent for early diagnosis of Mtb infection. In addition, when used in combination therapy with current ß-lactam antibiotics is expected that it will be possible to effectively combt MDR and XDR strains of Mtb.