BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections
Shahul Hameed P, Harish Kaushik Kotakonda, Sreevalli Sharma, Radha Nandishaiah, Nainesh Katagihallimath, R. Jagadiswara Rao, C Sadler, Ian Slater, Michael J. Morton, Abhijeeth Chandrasekaran, Ed Griffen, Dhanashree Pillai, Sambasiva Reddy, Nagakumar Bharatham, Venkatesan Suryanarayanan, Venugopal Jonnalagadda, Ramesh Jayaraman, Mahesh Nanjundappa, Maitrayee Sharma, Savitha Raveendran, Sreenath Rajagopal, Harikrishna Tumma, Amy A. Watters, H. D. Becker, Jill Lindley, Robert K. Flamm, Michael D. Huband, Dan Sahm, Meredith Hackel, Tarun Mathur, Ruwanthi Kolamunnage-Donà, Jennifer Unsworth, Laura McEntee, Nikki Farrington, Dhanasekaran Manickam, N Chandrashekara, Sivakandan Jayachandiran, Hrushikesava Reddy, S. Shanker, Vijay Richard, Teby Thomas, Savitha Nagaraj, Santanu Datta, Vasan K. Sambandamurthy, Vasanthi Ramachandran, Robert Clay, John Tomayko, Shampa Das, V Balasubramanian
Abstract
The global crisis of antimicrobial resistance (AMR) necessitates the development of broad-spectrum antibacterial drugs effective against multi-drug resistant (MDR) pathogens. BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI) selectively inhibits bacterial DNA replication via inhibition of DNA gyrase and topoisomerase IV. BWC0977 exhibited a minimum inhibitory concentration (MIC90) of 0.03–2 µg/mL against a global panel of MDR Gram-negative bacteria including Enterobacterales and non-fermenters, Gram-positive bacteria, anaerobes and biothreat pathogens. BWC0977 retains activity against isolates resistant to fluoroquinolones (FQs), carbapenems and colistin and demonstrates efficacy against multiple pathogens in two rodent species with significantly higher drug levels in the epithelial lining fluid of infected lungs. In healthy volunteers, single-ascending doses of BWC0977 administered intravenously ( https://clinicaltrials.gov/study/NCT05088421 ) was found to be safe, well tolerated (primary endpoint) and achieved dose-proportional exposures (secondary endpoint) consistent with modelled data from preclinical studies. Here, we show that BWC0977 has the potential to treat a range of critical-care infections including MDR bacterial pneumonias. In this work, the authors probe the efficacy of BWC0977, a bacterial topoisomerase inhibitor, in pre-clinical animal models, also demonstrating that BWC0977 is safe and well tolerated in healthy human volunteers, in a phase 1 trial.