Affiliation: | 1. Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St SE, Minneapolis, Minnesota 55455 USA;2. Department of Microbiology, Immunology, University of Minnesota Medical School, 689 23rd Ave SE, Minneapolis, Minnesota 55455 USA;3. Department of Medicinal Chemistry, University of Minnesota, 308 Harvard St SE, Minneapolis, Minnesota 55455 USA Department of Biotechnology, Gandhi Institute of Technology and Management (GITAM) School of Science, Deemed to be University, Gandhi nagar, Rushikonda, Visakhapatnam-530045, Andhra Pradesh, India;4. Department of Microbiology, Immunology, University of Minnesota Medical School, 689 23rd Ave SE, Minneapolis, Minnesota 55455 USA Department of Microbiology, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi 470-1192 Japan |
Abstract: | Tuberculosis (TB) is a leading source of infectious disease mortality globally. Antibiotic-resistant strains comprise an estimated 10 % of new TB cases and present an urgent need for novel therapeutics. β-lactam antibiotics have traditionally been ineffective against M. tuberculosis (Mtb), the causative agent of TB, due to the organism's inherent expression of β-lactamases that destroy the electrophilic β-lactam warhead. We have developed novel β-lactam conjugates, which exploit this inherent β-lactamase activity to achieve selective release of pyrazinoic acid (POA), the active form of a first-line TB drug. These conjugates are selectively active against M. tuberculosis and related mycobacteria, and activity is retained or even potentiated in multiple resistant strains and models. Preliminary mechanistic investigations suggest that both the POA “warhead” as well as the β-lactam “promoiety” contribute to the observed activity, demonstrating a codrug strategy with important implications for future TB therapy. |