Researchers from Rutgers University have identified a group of compounds that may stop tuberculosis from becoming drug-resistant.
Rutgers University researchers may have found a way to target multidrug-resistant Mycobacterium tuberculosis (TB).
The World Health Organization (WHO) has ranked TB as one of the leading causes of death on a global scale. Indeed, the infection killed 1.8 million individuals in 2015. Rifampin is one of two first-line anti-TB drugs that have been successful in treating the respiratory infection. However, resistance to rifampin, as well as isoniazid—the other first-line anti-TB drug—is growing, and has made TB a public health threat. In fact, WHO estimates that in 2015, around 480,000 individuals had developed a multidrug-resistant form of TB.
TB becomes resistant to rifampin when Mtb RNA polymerase (Mtb RNAP), the bacterial enzyme to which the drug usually binds, mutates, thus preventing the drug’s ability to inhibit and kill the bacteria.
Researchers from around the world have been working tirelessly to achieve two main goals: identify “improved rifampin derivatives” to which alterations in the TB enzyme would not impact drug efficacy, and develop new inhibitors that bind to the same enzyme as rifampin but on different binding sites. Nevertheless, because of insufficient data, “rational, structure-based drug discovery for Mtb RNAP” has been “impossible,” until now.
According to a press release, researchers from Rutgers University report that they have identified “the three-dimensional structure of Mtb RNAP and Mtb RNAP bound to rifampin.” The researchers were able to “reveal the interactions between Mtb RNAP and rifampin, reveal the mechanism by which rifampin inhibits Mtb RNAP, and enable rational, structure-based design of improved rifampin derivatives for inhibition of Mtb RNAP.”
In addition, the group has also identified compounds that they hope would lead to the development of new anti-TB drugs that may be able to eliminate drug-resistant TB: Na-aroyl-N-aryl-phenylalaninamides (AAPs). The researchers found that these compounds can inhibit Mtb RNAP by binding to the enzyme at a different site than where rifampin binds, and kill TB bacteria, even rifampin-resistant TB. Furthermore, the compounds can be coadministered with rifampin to hinder the development of resistance to the first-line TB drug.
“AAPs represent an entirely new class of Mtb RNAP inhibitors and are, without question, the most promising Mtb RNAP inhibitors for anti-TB drug development since rifampin. We are very actively pursing AAPs. We have synthesized and evaluated more than 600 novel AAPs and have identified AAPs with high potencies and favorable intravenous and oral pharmacokinetics,” Board of Governors Professor of Chemistry and Chemical Biology and Laboratory Director at the Waksman Institute of Microbiology at Rutgers, and study coauthor, Richard H. Ebright, PhD, said when speaking about the study in the press release.
Commenting on the importance of these findings, Nader Fotouhi, PhD, Chief Scientific Officer at the Global Alliance for TB Drug Development, said "The discovery of an alternative binding site and the AAPs represents a significant step towards the identification of a novel RNAP inhibitor that would behave like rifampin but be devoid of any pre-existing resistance. The co-crystal structure of AAP and Mtb RNAP is a critical stepping stone for the design of next generation RNAP inhibitors."