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TB R&D Weekly Update: Expanding Our Options for TB Treatment

For this week’s update, we highlight three recent articles that look at repurposing and optimizing drugs already on the market or looking at novel targets and drug classes for TB.

Dooley KE, Mitnick C, Degroote MA, Obuku E, Belitsky V, Hamilton CD, Makhene M, Shah S, Brust JC, Durakovic N, Nuermberger E; on behalf of the Efficacy Subgroup, RESIST-TB. Old drugs, new purpose: Retooling existing drugs for optimized treatment of resistant tuberculosis. Clin Infect Dis. 2012 May 21. [Epub ahead of print]

  • Summary: Based on review of existing in vitro, animal, and human studies, this article highlights key knowledge gaps and provides prioritized recommendations for new preclinical and clinical trials to inform current treatment of drug-resistant tuberculosis and future clinical trials of investigational agents. Abstract: Treatment of drug-resistant tuberculosis (DR-TB) is hindered by the high toxicity and poor efficacy of second-line drugs. New compounds must be used together with existing drugs, yet clinical trials to optimize combinations of drugs for DR-TB are lacking. We conducted an extensive review of existing in vitro, animal, and clinical studies involving WHO-defined Group 1, 2, and 4 drugs used in DR-TB regimens to inform clinical trials and identify critical research questions. Results suggest optimizing the dosing of pyrazinamide, the injectables, and isoniazid for DR-TB is a high priority. Additional pharmacokinetic, pharmacodynamic and toxicodynamic studies are needed for pyrazinamide and ethionamide. Clinical trials of the comparative efficacy and appropriate treatment duration of injectables are recommended. For isoniazid, rapid genotypic tests for M. tuberculosis mutations should be nested in clinical trials. Further research focusing on optimization of dose and duration of drugs with activity against DR-TB is paramount.

Buroni S, Pasca MR, de Jesus Lopes Ribeiro AL, Degiacomi G, Molteni E, Riccardi G. Antituberculars which target decaprenylphosphoryl-β-D-ribofuranose 2′-oxidase DprE1: state of art. Appl Microbiol Biotechnol. 2012 May;94(4):907-16. Epub 2012 Apr 18.

  • Abstract: Multidrug resistance is a major barrier in the battle against tuberculosis and still a leading cause of death worldwide. In order to fight this pathogen, two routes are practicable: vaccination or drug treatment. Vaccination against Mycobacterium tuberculosis with the current vaccine Mycobacterium bovis Bacillus Calmette-Guerin is partially successful, being its efficacy variable. A few new tuberculosis vaccines are now in various phases of clinical trials. The emergence of multidrug-resistant strains of M. tuberculosis gave the impulse to discover new effective antitubercular drugs, a few of which are in clinical development. Here we focus on three different classes of very promising antitubercular drugs recently discovered (benzothiazinones, dinitrobenzamides, and benzoquinoxalines) that share the same cellular target: a subunit of the heteromeric decaprenylphosphoryl-β-D: -ribose 2′-epimerase, encoded by the dprE1 (or Rv3790) gene. This enzyme is involved in the biosynthesis of D: -arabinose which is crucial for the synthesis of the mycobacterial cell wall and essential for the pathogen’s survival.

Stanley SA, Schmidt Grant S, Kawate T, Iwase N, Shimizu M, Wivagg C, Silvis M,Kazyanskaya E, Aquadro J, Golas A, Fitzgerald M, Dai H, Zhang L, Hung DT. Identification of Novel Inhibitors of M. tuberculosis Growth Using Whole Cell Based High-Throughput Screening. ACS Chem Biol. 2012 May 21. [Epub ahead of print]

  • Abstract: Despite the urgent need for new antitubercular drugs, few are on the horizon. To combat the problem of emerging drug resistance, structurally unique chemical entities that inhibit new targets will be required. Here we describe our investigations using whole cell screening of a diverse collection of small molecules as a methodology for identifying novel inhibitors that target new pathways for Mycobacterium tuberculosis drug discovery. We find that conducting primary screens using model mycobacterial species may limit the potential for identifying new inhibitors with efficacy against M. tuberculosis. In addition, we confirm the importance of developing in vitro assay conditions that are reflective of in vivo biology for maximizing the proportion of hits from whole cell screening that are likely to have activity in vivo. Finally, we describe the identification and characterization of two novel inhibitors that target steps in M. tuberculosis cell wall biosynthesis. The first is a novel benzimidazole that targets mycobacterial membrane protein large 3 (MmpL3), a proposed transporter for cell wall mycolic acids. The second is a nitro-triazole that inhibits decaprenylphosphoryl-β-d-ribose 2′-epimerase (DprE1), an epimerase required for cell wall biosynthesis. These proteins are both among the small number of new targets that have been identified by forward chemical genetics using resistance generation coupled with genome sequencing. This suggests that methodologies currently employed for screening and target identification may lead to a bias in target discovery and that alternative methods should be explored.

Additional TB R&D News:

The Stop TB Partnership and The Lilly MDR-TB Partnership, in Conjunction with Innosight, to Convene Multi-Drug Resistant Tuberculosis Innovation Summit

Experimental vaccine elicits robust response against both HIV and tuberculosis

Antibiotics: Recover the lost art of drug discovery

Work starts on $30 million TB hospital in Afghanistan

982 diagnostic centres set up for TB patients (Islamabad)

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