Nature Communications (Sep 2024)

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

  • Shahul Hameed P,
  • Harish Kotakonda,
  • Sreevalli Sharma,
  • Radha Nandishaiah,
  • Nainesh Katagihallimath,
  • Ranga Rao,
  • Claire Sadler,
  • Ian Slater,
  • Michael Morton,
  • Abhijeeth Chandrasekaran,
  • Ed Griffen,
  • Dhanashree Pillai,
  • Sambasiva Reddy,
  • Nagakumar Bharatham,
  • Suryanarayanan Venkatesan,
  • Venugopal Jonnalagadda,
  • Ramesh Jayaraman,
  • Mahesh Nanjundappa,
  • Maitrayee Sharma,
  • Savitha Raveendran,
  • Sreenath Rajagopal,
  • Harikrishna Tumma,
  • Amy Watters,
  • Holly Becker,
  • Jill Lindley,
  • Robert Flamm,
  • Michael Huband,
  • Dan Sahm,
  • Meredith Hackel,
  • Tarun Mathur,
  • Ruwanthi Kolamunnage-Dona,
  • Jennifer Unsworth,
  • Laura Mcentee,
  • Nikki Farrington,
  • Dhanasekaran Manickam,
  • Narayana Chandrashekara,
  • Sivakandan Jayachandiran,
  • Hrushikesava Reddy,
  • Sathya Shanker,
  • Vijay Richard,
  • Teby Thomas,
  • Savitha Nagaraj,
  • Santanu Datta,
  • Vasan Sambandamurthy,
  • Vasanthi Ramachandran,
  • Robert Clay,
  • John Tomayko,
  • Shampa Das,
  • Balasubramanian V

DOI
https://doi.org/10.1038/s41467-024-52557-2
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 20

Abstract

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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.