Synthesis of narrow-spectrum anti-mycobacterial molecules without effect on the diversity of gut microbiota in mice based on the structure of rifampicin.

ABSTRACT

Rifampicin (RIF) is a broad-spectrum antimicrobial agent that is also a first-line drug for treating tuberculosis (TB). Based on the naphthyl ring structure of RIF this study synthesized 16 narrow-spectrum antimicrobial molecules that were specifically anti-Mycobacterium tuberculosis (Mtb). The most potent candidate was 2-((6-hydroxynaphthalen-2-yl) methylene) hydrazine-1-carbothioamide (compound 3c) with minimum inhibitory concentration (MIC) of 1 µg/mL against Mtb. Synergistic anti-Mtb test indicated that none of the combinations of 3c with the major anti-TB drugs are antagonistic. Consistent with RIF, compound 3c induced large amounts of reactive oxygen radicals (ROS) in the cells of Mtb. The killing kinetics of compound 3c and RIF are very similar. Furthermore, molecular docking showed that compound 3c was able to access the RIF binding pocket of the ß subunit of Mtb RNA polymerase (RNAP). Experiments in mice showed that compound 3c increased the variety of intestinal flora in mice, while RIF significantly decreased the diversity of intestinal flora in mice. In addition, compound 3c is non-toxic to animal cells with a selection index (SI) much more than 10. The evidence from this study suggests that the further development of 3c could contribute to the development of novel drug for TB treatment.