Discovery of benzophenanthridine derivatives with potent activity against multidrug resistant Mycobacterium tuberculosis

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 (BPD). The two most potent compounds, BPD-6 and BPD-9, accumulated within the bacterial cell and exhibited strong inhibitory activity (MIC90 [~] 2-10 M) 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 viability within infected macrophages. The two BPD compounds displayed comparable efficacy to rifampicin, a critical frontline antibiotic used for the prevention and treatment of TB. Importantly, BPD-6 and BPD-9 inhibited the growth of multiple MDR Mtb clinical isolates, suggesting a completely novel mechanism of action compared to existing frontline TB dugs. The discovery of BPDs provides novel chemical scaffolds for anti-TB drug discovery. TOC/GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=110 SRC="FIGDIR/small/515485v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@1536acaorg.highwire.dtl.DTLVardef@1881e83org.highwire.dtl.DTLVardef@18b2f58org.highwire.dtl.DTLVardef@d15f1a_HPS_FORMAT_FIGEXP M_FIG C_FIG