Therapeutics for Tuberculosis: Novel Inhibitors of Mycobacterial RNA Polymerase

Invention Summary: Tuberculosis kills nearly 2 million persons each year.  One third of the world's population currently is infected with tuberculosis, and the World Health Organization projects that there will be nearly 1 billion new infections by 2020, 200 million of which will result in serious illness, and 35 million of which will result in death.  Treatment of tuberculosis infections is slow (minimum treatment period of six months), and treatment of multi-drug-resistant (MDR) and extensively-drug-resistant (XDR) tuberculosis infections is very slow and often ineffective (minimum treatment time of twelve months and mortality greater than 50%). There is an urgent need for new classes of antituberculosis agents, particularly antituberculosis agents that clear infection quickly and are effective against MDR and XDR infections. Rutgers researchers have identified a class of compounds that potently inhibit Mycobacterial RNA polymerase (RNAP) but do not potently inhibit Gram-negative bacterial RNAP or other Gram positive bacterial RNAP: N α -aroyl-N-aryl-phenylalaninamides (AAPs). Rutgers researchers have validated AAPs as lead compounds; have synthesized and evaluated more than 600 novel AAPs; have identified novel AAPs that exhibit improved potencies, physical properties, and pharmacological properties; and have demonstrated in vivo proof of concept in a mouse tuberculosis acute infection model. Market Applications: Treatment of tuberculosis, including MDR and XDR tuberculosis Treatment of non-tuberculosis mycobacterial (NTM) infections, including Mycobacterium avium complex (MAC) infections Advantages: First-in-class compounds Novel target and mechanism Potent selective antimycobacterial activity Activity against MDR and XDR strains Activity against both replicating and non-replicating mycobacteria Rapid sterilizing activity Additive effects when co-administered with current antituberculosis agents Suppressed resistance emergence when co-administered with current antituberculosis agents Intellectual Property & Development Status: Patent coverage of new compositions of matter. Advanced lead compounds with in vivo proof of concept in animal tuberculosis infection models.