Identification of a small molecule with activity against drug-resistant and persistent tuberculosis

Feng Wang, Dhinakaran Sambandan, Rajkumar Halder et al.

Proc Natl Acad Sci USA. 2013. 110: 10879-10880

Speaker: Yu-Chi Ho (賀聿齊)                                       Time: 15:10~16:00, Oct. 2, 2013

Commentator: Dr. Liu, Ching-Chuan (劉清泉 博士)              Place: Room 601

Abstract

   Mycobacterium tuberculosis (Mtb) has been associated with human disease for thousands of years. This organism is able to persist for long time in human body that lends the opportunities for the multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains to emerge and spread, resulting in loss of effectiveness by current therapies (1). A new drug with reduced time of treatment and therefore is able to overcome the emergence of resistance is urgently needed. To identify new molecules inhibiting biofilm formation, which is observed during a chronic infection byMtb, and growth of Mtb, the authors used high-throughput cell-based screening under biofilm culture conditions. They screened 70,000 heterocycle compounds and selected a molecule, TCA1, which displayed potent inhibitory activity against Mtb under biofilm culture condition and showed bactericidal activity specific to Mycobacterium. TCA1 kills both replicating (WT and drug resistant) and nonreplicating Mtb. It was also efficacious, either alone or combined with rifampicin (RIF) or isoniazid (INH), in acute and chronic Mtb infections in the mouse. To gain insight into the mechanism of action of TCA1, they conducted genome-wide transcriptional analysis of Mtb H37Rv treated with TCA1. Some of the down-regulated genes after TCA1 treatment were involved in dormancy and drug tolerance, suggesting that TCA1 may potentially make Mtb more susceptible to antibiotics. A few  TCA1-resistant mutants were later isolated and their genome sequences were determined. They all had a single-point mutation resulting in amino acid change in rv3790, which encodes DprE1, a component of decaprenyl-phosphoryl-β-D-ribofuranose 2′-epimerase, DprE1/DprE2, required for cell wall arabinan biosynthesis. These suggest that DprE1 may be a target of TCA1. They also used TCA1 analog, TCA17, to pull-down a protein that was then identified as MoeW, an enzyme involved in the biosynthesis of the molybdenum cofacter, MoCo. MoCo is essential for the nitrate respiratory and assimilatory functions of Mtb nitro-reductase (2). They demonstrated that the activity of TCA1 against Mtb is via inhibition of MoCo biosythesis by interaction with MoeW. In summary, this work shows a powerful improvement in searching for new compounds to deal with the persistent and drug-resistant TB, and TCA1 thus identified functions by inhibiting two distinct biosynthetic pathways.

References

1. Gandhi NR, et al. HIV coinfection in multidrug- and extensively drug-resistant tuberculosis results in high early mortality. Am J Respir Crit Care Med 181(1):80–86.(2010)

2. Williams MJ. et al. Functional analysis of molybdopterin biosynthesis in mycobacteria identifies a fused molybdopterin synthase in Mycobacterium tuberculosis. J Bacteriol 193(1):98–106.(2011)