BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections

• Published in: Nature communications Vol. 15; no. 1; pp. 8202 - 20
• Main Authors: Hameed P, Shahul, Kotakonda, Harish, Sharma, Sreevalli, Nandishaiah, Radha, Katagihallimath, Nainesh, Rao, Ranga, Sadler, Claire, Slater, Ian, Morton, Michael, Chandrasekaran, Abhijeeth, Griffen, Ed, Pillai, Dhanashree, Reddy, Sambasiva, Bharatham, Nagakumar, Venkatesan, Suryanarayanan, Jonnalagadda, Venugopal, Jayaraman, Ramesh, Nanjundappa, Mahesh, Sharma, Maitrayee, Raveendran, Savitha, Rajagopal, Sreenath, Tumma, Harikrishna, Watters, Amy, Becker, Holly, Lindley, Jill, Flamm, Robert, Huband, Michael, Sahm, Dan, Hackel, Meredith, Mathur, Tarun, Kolamunnage-Dona, Ruwanthi, Unsworth, Jennifer, Mcentee, Laura, Farrington, Nikki, Manickam, Dhanasekaran, Chandrashekara, Narayana, Jayachandiran, Sivakandan, Reddy, Hrushikesava, Shanker, Sathya, Richard, Vijay, Thomas, Teby, Nagaraj, Savitha, Datta, Santanu, Sambandamurthy, Vasan, Ramachandran, Vasanthi, Clay, Robert, Tomayko, John, Das, Shampa, V, Balasubramanian
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 18.09.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/154/309/2144; 64/60; 64/86; 692/699/255/1318; Adult; Anaerobes; Animal models; Animals; Anti-Bacterial Agents - administration & dosage; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antiinfectives and antibacterials; Antimicrobial resistance; Bacteria; Carbapenems; Colistin; Deoxyribonucleic acid; DNA; DNA biosynthesis; DNA topoisomerase; DNA topoisomerase inhibitors; DNA topoisomerase IV; Drug development; Drug resistance; Drug Resistance, Multiple, Bacterial - drug effects; Effectiveness; Female; Fermenters; Fluoroquinolones; Gram-negative bacteria; Gram-Negative Bacteria - drug effects; Gram-positive bacteria; Gram-Positive Bacteria - drug effects; Healthy Volunteers; Humanities and Social Sciences; Humans; Inhibitors; Male; Mice; Microbial Sensitivity Tests; Middle Aged; Minimum inhibitory concentration; multidisciplinary; Multidrug resistance; Pathogens; Rats; Science; Science (multidisciplinary); Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52557-2

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 (MIC 90 ) 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.