Mycobacterium tuberculosis cause tuberculosis. Tuberculosis often affects the lungs. Tuberculosis spreads from person to person through the air. When people with lung tuberculosis cough, sneeze or spit, they propel the tuberculosis germs into the air. A person needs to inhale only a few of these germs to become infected. However persons with compromised immune systems, such as people living with HIV, malnutrition or diabetes, have a much higher risk of falling ill. When a person develops active tuberculosis (disease), the symptoms (cough, fever, night sweats, weight loss etc.) may be mild for many months. This can lead to delays in seeking care, and results in transmission of the bacteria to others. Tuberculosis is curable and preventable. However, tuberculosis can develop resistance to the antimicrobial drugs used to cure the disease. Multidrug-resistant tuberculosis is tuberculosis that does not respond to at least Isoniazid and Rifampicin, the 2 most powerful anti-tuberculosis drugs.
Resistance to tuberculosis drugs is a formidable obstacle to effective tuberculosis care and prevention globally. Multidrug-resistant tuberculosis is multi-factorial. Consequently, Bedaquiline is the first example of a class of drug that has proven clinically effective against drug-resistant tuberculosis. Bedaquiline has a novel mechanism of action, selectively inhibiting the myco-bacterial ATP synthase-enzyme.
In this study, Hamish S.Sutherland, et al presented compounds demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated human Ether-a-go-go Related Gene (hERG) blockade. Of these, TBAJ-587 is a potent antituberculosis agent. In particular, TBAJ-587 inhibits hERG channel minimally and attenuates inhibition of the cardiac potassium channel protein coded by the hERG, which is important for cardiac repolarization. Gratifyingly, the efficacy demonstrates against murine tuberculosis at lower exposures than Bedaquiline in mice. In summary, TBAJ-587 is a potent anti-tuberculosis agent with minimal inhibition of the hERG channel.
Sutherland HS, et al. 3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel. Bioorg Med Chem. 2019 Apr 1;27(7):1292-1307.