Programs to Facilitate Tuberculosis Drug Discovery: The Tuberculosis Antimicrobial Acquisition and Coordinating Facility

Abstract

There is a real need to discover new drugs that are active on drug-resistant tuberculosis (TB), and for drugs that will shorten the time of therapy. Large pharmaceutical companies have traditionally led the quest for discovering and developing new antiinfective agents but this is not the case when it comes to diseases like tuberculosis that primarily occur in resource restricted countries. Throughout the world many research groups are actively engaged in the scientific discovery of new TB drugs. Unfortunately, most research laboratories do not have the necessary safety facilities or resources for all facets of TB drug discovery. The Tuberculosis Antimicrobial Acquisition and Coordinating Facility (TAACF) was established in order to make comprehensive testing services available at no cost to research laboratories with an interest in discovering new TB drugs. The TAACF is a consortium of contracts managed and funded by the National Institute of Allergy and Infectious Diseases (National Institutes of Health, Bethesda, MD) as a resource to support preclinical drug discovery and development. The core of the TAACF is the Southern Research Institute, Birmingham, AL, which supports compound acquisition, storage, medicinal chemistry, and high throughput assays. Other collaborating groups provide biological data on antimycobacterial activity and cytotoxicity, preliminary in vivo toxicity, oral bioavailability and efficacy in animal models, specialty testing (such as activity against non-replicating persistent bacteria), and assistance in technology transfer for developing comprehensive promotional packages and facilitating partnerships with pharmaceutical companies for drug development. The TAACF program and recent progress that has been publicly disclosed by suppliers is reviewed. There are many aspects promising of the program that will not be discussed due to confidentially.

SQ109 Targets MmpL3, a Membrane Transporter of Trehalose Monomycolate Involved in Mycolic Acid Donation to the Cell Wall Core of Mycobacterium tuberculosis

“…The compounds DA5 (SRI 356596) and DA8 (SRI 391844) were initially identified in a screen for growth inhibition of M. tuberculosis which was run at the Southern Research Institute as part of the MLPCN program and part of the Tuberculosis Antimicrobial Acquisition and Coordinating Facility program contracts N01-AI-95364 and NO1-AI-15449 (24). M. tuberculosis mutants resistant to DA5 and DA8 were isolated by plating 10-fold serial dilutions of liquid cultures grown to an OD 600 of ϳ1.5 onto plates containing 40 M DA5 and 21.1 or 42.2 M DA8, respectively.…”

Quinoxaline 1,4-di-N-Oxide and the Potential for Treating Tuberculosis

“…metronidazole, PA-824 and OPC-67683), it appeared logical to us to evaluate our group of structures against mycobacteria [9].…”

“…Over 87,000 compounds have been supplied to TAACF, of which only 0.9% have shown a good in vitro activity/toxicity ratio [9]. One of five lead compound series which were identified and are currently been pursued under the TAACF program is the series of quinoxaline 1,4-di-N-oxide derivatives.…”

“…Over 500 quinoxaline derivatives from our laboratory were tested by the TAACF program, including simple substituted quinoxalines and their corresponding 1,4-di-N-oxides. Many of these compounds possess excellent antitubercular activity, and the range of possible substituents affords an opportunity to tailor both the pharmacokinetic and activity profiles [9].…”

“…These screening activities have resulted in several promising agents that have reached advanced stages of testing [9]. Chart 1 shows the preliminary levels of biological assays and cut-offs applied by TAACF for progression of the compounds in tuberculosis drug screening program.…”