This week in TB R&D – 12 April 2010

12 Apr 2010
by Working Group

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On April 6th, the New York Academy of Sciences hosted a mini-symposium entitled ‘Tuberculosis: Novel Therapies through Knowledge of the Genetics of the Causative Agent.’ The five research scientists who presented were: William R. Jacobs, Jr. (Albert Einstein College of Medicine), Christopher Sassetti (University of Massachusetts Medical School), Dirk Schnappinger (Weill Cornell Medical College), Helena Boshoff (National Institutes of Health, NIAID), and Carl Nathan (Weill Cornell Medical College). More than 130 people registered for the symposium and it was broadcasted to 16 different sites by a webinar including British Columbia, California, Italy, and India.

A brief summary of the presented research is highlighted below.

Bill Jacobs began his talk about rising XDR-TB infections and spread in Tugela Ferry, a town in central KwaZulu-Natal, South Africa. He emphasized the needs for rapid diagnostic tools for all strains of TB, new drugs, shorter drug treatments and new TB vaccines. He also emphasized the need to encourage more young African scientists. Bill shared a bit of his work on the use of mycobacteriophages to better understand and study M. tb and the use of GFP as a rapid diagnostic tool for TB infection. The rest of his presentation focused on his current investigations with collaborators to identify novel drug targets that led to the identification and characterization of the function and genetic networks surrounding, GlgE, an enzyme enzyme involved in the multi-step conversion of the di-saccharide thehalose to polymer alpha-glucans in M. tb.

Chris Sassetti started his talk with an overview of the TraSH (transposon site hybridization) approach his lab uses to understand the ‘eating’ (i.e. metabolism) and ‘sleeping’ (i.e. dormancy) of M. tb. To summarize, he uses forward genetics to identify genes and then determine functions of those genes in order to illuminate the bacteria’s lifestyle. After an introduction to the technique, Chris focused on the mammalian cell entry (mce) operons, specifically Mce4 and the intracellular growth (igr) genes and how these genes influence bacterial metabolism. The second half of the presentation focused on the no doze (ndz) and triglyceride synthesase mutants and their proposed roles in bacterial dormancy.

Dirk Schnappinger’s presentation centered on the power of in vivo genetic manipulation to test the function of interesting genes thought to be required for acute and chronic stage M. tb infection. In a very nice success story that employed the Tet on/Tet off system, his lab successfully generated mice with the ability to silence biotin A (bioA), a key regulator for fatty acid biosynthesis, and described the “knock-down” phenotype. He also described work using this approach to understand ClpXP, a serine protease complex necessary for M. tb pathogenicity.

Helen Boshoff shared insights into the high-throughput screening approach being used at the NIH for TB drug discovery. She highlighted that most TB-related screens to date have been ‘target-based” screens (i.e. identifying compounds that perturb a specific M. tb protein) and these have not been very successful in producing viable compounds for the clinic. By contrast, the approach currently being pursued by the NIH utilizes phenotypic screens (i.e. analyzing how compounds impact bacterial growth or survival), which have tended to be more successful in generating useful clinical compounds.

Carl Nathan was the final speaker for the afternoon. His talk focused on approaches to identify drugs which can target and kill non-replicating M. tb. Carl spotlighted work started by Omar Vandal, a postdoc in the lab, on cellular phagolysosomal pH changes important for the elimination of TB. A cell based screening assay which responds to changes in pH was developed in the lab and used to screen for compounds which override M. tb prevention of phagolysosomal pH decrease. The screen was optimized and sent to Lilly for additional compound screening.

Please check the NYAS meeting site in the next few weeks for the slide presentations.

Are there any meetings that you have recently attended? The WGND blog is a TB R&D community resource, and intended to increase virtual collaboration and discussions. Please feel free to submit overviews of research presentations you’ve attended.

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