pubs.acs.org
Evolution of Small Molecule Inhibitors of Mycobacterium tuberculosis Menaquinone Biosynthesis
A dire need exists for novel drugs to treat Mycobacterium tuberculosis infection. In an effort to build on our early efforts targeting the MenG enzyme within the menaquinone biosynthetic pathway, we have pursued the optimization of diaryl amide JSF-2911 to address its poor metabolic stability and modest in vitro potency. A hit evolution campaign focused on modification of the amine substructure within this hit compound, resulting in a range of analogues that have been profiled extensively. Among these derivatives, JSF-4536 and JSF-4898 demonstrated significantly improved biological profiles, notably offering submicromolar MIC values versus M. tuberculosis and promising values characterizing the mouse liver microsome stability, aqueous solubility, and mouse pharmacokinetic profile. JSF-4898 enhanced the efficacy of rifampicin in a subacute model of M. tuberculosis infection in mice. The findings suggest a rationale for the further optimization of MenG inhibitors to provide a novel therapeutic strategy to address M. tuberculosis infection.
![In 1956, L. Ferenczy published a paper documenting that plant seeds from various plant species, including those from Cannabis sativa, exhibited antibacterial activity, especially against Gram-positive bacteria [64]. Wasim et al. [65] documented that both ethanolic and petroleum ether extracts of Cannabis sativa leaves showed anti-microbial activity against Bacillus subtilis, Staphylococcus aureus, Micrococcus flavus, Bordetella bronchiseptica, Proteus vulgaris, Aspergillus niger, and Candida albicans. Ali et al. [66] observed that the oil of the seeds of Cannabis sativa exerted pronounced anti-bacterial activity against Bacillus subtilis and Staphylococcus aureus, with moderate activity against Escherichia coli and Pseudomonas aeruginosa, without any activity against Aspergillus niger and Candida albicans.](https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:6axy7wdlfc75pqptdsttgrfw/bafkreihmybunimislywz6t3yglimg42joj5wceo4opo4royudbigreloeu)
![Nissen et al. [34] observed that essential oils of Cannabis sativa L., prepared from 50–70% of seed maturity, showed anti-bacterial activity against the Gram-positive bacteria Enterococcus faecium and Streptococcus salivarius at less than 1% (v/v) but were unable to inhibit the growth of the yeast Saccharomyces cerevisiae. Zengin et al. [68] found that essential oils distilled from leaves, inflorescences, and thinner stems of the hemp plant showed anti-oxidative properties and had significant anti-bacterial activity against clinical Helicobacter pylori strains (MIC = 16–64 μg/mL), with lower activity against clinical Staphylococcus aureus isolates (MIC = 8 mg/mL) and no significant activity against Candida spp. and Malassezia spp. The minimum bacterial biofilm inhibitory concentration (MBIC) of the hemp essential oil against Helicobacter pyroli was similar to the MIC [68]. The hemp essential oil showed cytotoxicity against human breast cancer, cholangiocarcinoma, and colon carcinoma ce](https://cdn.bsky.app/img/feed_thumbnail/plain/did:plc:6axy7wdlfc75pqptdsttgrfw/bafkreibtxcjc6zbjw4w2jfgbzg2rt52fdq47wjeqfgwklfaujvjvpbeto4)
