2024-10-08 カナダ・ブリティッシュコロンビア大学(UBC)
<関連情報>
- https://news.ubc.ca/2024/10/modified-plant-compound-next-weapon-in-fight-against-drug-resistant-tb/
- https://journals.asm.org/doi/10.1128/spectrum.01246-24
多剤耐性結核菌に対して強力な活性を示すベンゾ[c]フェナントリジン誘導体の発見 Discovery of benzo[c]phenanthridine derivatives with potent activity against multidrug-resistant Mycobacterium tuberculosis
Yi Chu Liang, Zhiqi Sun, Chen Lu, Andréanne Lupien, Zhongliang Xu, Stefania Berton, Peng Xu, Marcel A. Behr, Weibo Yang, Jim Sun
Microbiology Spectrum Published:3 October 2024
DOI:https://doi.org/10.1128/spectrum.01246-24
ABSTRACT
Mycobacterium tuberculosis (Mtb), the pathogen responsible for tuberculosis (TB), is the leading cause of bacterial disease-related death worldwide. Current antibiotic regimens for the treatment of TB remain dated and suffer from long treatment times as well as the development of drug resistance. As such, the search for novel chemical modalities that have selective or potent anti-Mtb properties remains an urgent priority, particularly against multidrug-resistant (MDR) Mtb strains. Herein, we design and synthesize 35 novel benzo[c]phenanthridine derivatives (BPDs). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 ~2 to 10 µM) against multiple Mycobacterium strains while remaining inactive against a range of other Gram-negative and Gram-positive bacteria. BPD-6 and BPD-9 were also effective in reducing Mtb survival within infected macrophages, and BPD-9 reduced the burden of Mycobacterium bovis BCG in the lungs of infected mice. The two BPD compounds displayed comparable efficacy to rifampicin (RIF) against non-replicating Mtb (NR-Mtb). Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates. Generation of BPD-9-resistant mutants identified the involvement of the Mmr efflux pump as an indirect resistance mechanism. The unique specificity of BPDs to Mycobacterium spp. and their efficacy against MDR Mtb isolates suggest a potential novel mechanism of action. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery.
