New weapons for the war against tuberculosis
According to the World Health Organization (WHO), TB comes in second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent (Mycobacterium tuberculosis (Mtb)). Until the recent approval of bedquiline, no new drugs for TB had been approved for over 40 years and treatment requires a regimen of 4 different drugs administered over a period of at least 6 months. Aside from issues of drug resistance, the treatment regimen does not favour a high success rate. Novel and more effective drugs are urgently needed. A promising target is the Mtb cell wall, a thick and impermeable barrier against environmental stress and the action of many drugs. Mtb produces decaprenyl-phosphoryl arabinose (DPA), the sole donor of a type of cell wall sugar and thus critical for cell wall biosynthesis. Without it, the bacterium cannot survive. A novel drug (BTZ043) that blocks DPA biosynthesis through the inhibition of a specific enzyme (DprE1) is in the late stages of pre-clinical development. Scientists investigated its mechanisms of action in detail to develop other such inhibitors with EU funding of the DPRETB project. One line of work involved developing a clear understanding of the detailed structure of the target given that the drug inhibits activity via binding in a lock-and-key fashion. Crystallisation of the drug-target complex provided a 3D structure of DprE1 and elucidated the binding mechanism. Results have been published in a peer-reviewed scientific journal. A second line of work focused on the synthesis and use of fluorescent analogues of BTZ043. When cultured Mtb was incubated with these fluorescenct compounds, high-intensity fluorescence at the poles was observed, consistent with expected cellular localisation of DprE1. A related assay is under development for high-throughput screening of libraries of compounds to replace current low-throughput methods. DPRETB has had impressive success elucidating the detailed mechanism of action of BTZ043 in inhibiting the survival of Mtb. Knowledge is being used to develop more novel TB drugs to combat this major public health threat whose treatment has essentially remained unchanged for more than 40 years.
