Identification of Novel Coumestan Derivatives as Pks13 Inhibitors against Mycobacterium Tuberculosis

Unmet Need
Tuberculosis (TB) is an infectious disease caused by the bacteria Mycobacterium tuberculosis (Mtb), which typically impacts the lungs. In 2016, there were 10.4 million new cases of TB and 1.7 million deaths worldwide, with approximately one-fourth of the world’s population infected. As a result, TB is one of the leading infectious disease killers and a serious public health problem. The typical treatment course for drug-sensitive TB has a duration of at least 6 months and incurs a direct cost of over $18,000 USD. However, the incidence of drug-resistant TB is greatly increasing, including multidrug-resistant (MDR), extensively drug resistant (XDR), and totally drug resistant (TDR) TB, presenting a major challenge to treating TB and controlling its transmission. Consequently, there is a critical need for the development of novel therapeutics and strategies for treating both drug-sensitive and drug-resistant TB.   
 
Technology Overview
Johns Hopkins researchers have identified coumestan analogues as novel compounds for treating TB that inhibit mycolic acid synthesis needed for generating the Mtb cell wall. These natural analogues demonstrated potent anti-TB activity in vitro, with low minimal inhibitory concentrations (MIC) for 90% inhibition. Good oral bioavailability of these compounds was observed in mice using a serum titration assay, and they were noncytotoxic to mammalian cells in vitro at concentrations far exceeding their MIC90 measured for Mtb. Whole genome sequencing of Mtb strains resistant to the coumestans revealed a single-nucleotide polymorphism in the polyketide synthase 13 gene (pks13), verifying Pks13 as the target for these analogues and druggability of Pks13 for the development of other antitubercular agents.   
 
Stage of Development
The inventors have identified novel, potential therapeutic compounds and their target for the treatment of TB. Further studies are required to determine efficacy against Mtb in vivo, toxicity in vivo, and their success in combination with other antitubercular drugs already in use.
 
Publications
Zhang W, et al. J. Med. Chem. 61, 791-803, 2018 
 

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