BWC0977: A New Approach to Antimicrobial Resistance

The global crisis of antimicrobial resistance (AMR) necessitates the urgent development of broad-spectrum antibacterial drugs that can effectively combat multi-drug resistant (MDR) pathogens. Among potential candidates, BWC0977, a Novel Bacterial Topoisomerase Inhibitor (NBTI), has shown promise in selectively inhibiting bacterial DNA replication through the inhibition of DNA gyrase and topoisomerase IV. The findings suggest that BWC0977 holds significant potential for the treatment of critical-care infections, including MDR bacterial pneumonias.

BWC0977 demonstrated an minimum inhibitory concentration (MIC90) range of .03–2 µg/mL against a variety of MDR pathogens. It retained activity against bacteria resistant to fluoroquinolones (FQs), carbapenems, and colistin. In vivo studies showed that BWC0977 was effective against multiple pathogens in two rodent species, achieving significantly higher drug levels in the epithelial lining fluid of infected lungs. Clinical trial results indicated that BWC0977 was safe and well tolerated in healthy volunteers, with dose-proportional exposures consistent with preclinical models.

In Contagion's recent interview with Bala Subramanian, PhD, COO and head of R&D at Bugworks at the World AMR Congress, he shed light on BWC0977, “It's a novel mechanism, and so the preexisting resistance, towards the beta lactams, carbapenems, none of that would matter here, because it has a completely different mechanism, and it's a truly broad spectrum. That's what differentiates this novel compound, it works against all gram negatives, gram positives, atypical bacteria, pathogens which are implicated in bioterrorism. It has a very wide repertoire in terms of the bugs that it targets, that's what differentiates it,” Bala stated.²

BWC0977 was evaluated for its MIC90 against a global panel of MDR Gram-negative bacteria, including Enterobacterales and non-fermenters, as well as Gram-positive bacteria, anaerobes, and biothreat pathogens. The drug's effectiveness against isolates resistant to FQs, carbapenems, and colistin was also assessed.

BWC0977 has recently completed its single ascending dose phase in healthy volunteers and is poised to begin the multiple ascending dose phase. “Currently, this drug has completed the single ascending dose in healthy volunteers. It is now about to start the multiple ascending dose phase,” Subramanian explained. The drug will be administered intravenously over a duration of seven days, twice daily.²

Preclinical studies provided model data that informed subsequent clinical evaluations. A clinical trial (NCT05088421) was conducted to assess the safety, tolerability, and dose-proportional exposure of single-ascending doses of BWC0977 administered intravenously to healthy volunteers.

Additionally, BWC0977 is being developed in an oral form, a feature that is rare among new antibiotics. “The same compound, BWC0977, is also coming in its oral form,” Subramanian noted. This dual formulation will enable critical care patients to switch from intravenous to oral medication, improving convenience and discharge options. The oral formulation is expected to enter first-time-in-human studies next year.²

BWC0977 efficacy against a broad spectrum of resistant pathogens, combined with a favorable safety profile in initial humanstudies, positions BWC0977 as a promising candidate in the fight against antimicrobial resistance.

References

1. Hameed P, S., Kotakonda, H., Sharma, S. et al. BWC0977, a broad-spectrum antibacterial clinical candidate to treat multidrug resistant infections. Nat Commun 15, 8202 (2024). https://doi.org/10.1038/s41467-024-52557-

2. Abene S, Subramanian B. Bugworks' Antibiotic BWC0977 Targets Resistant Pathogens. Contagion. September 6, 2024. Accessed Septmeber 18, 2024. https://www.contagionlive.com/view/bugworks-antibiotic-bwc0977-targets-resistant-pathogens