Search for new anti -TB molecules.

Despite the availability of antitubercular therapy for over 40 years, the incidence of TB has increased at an alarming rate in the last decade. Currently BCG is the only approved vaccine against tuberculosis. However, it is found to be less effective in preventing the disease in adults and the efficacy is relatively low in tropical third world countries. Emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) strains of Mycobacterium tuberculosis renders the current mode of treatment very difficult, prohibitively expensive and often completely ineffective. The situation is made worse by the lethal combination of drug-resistant TB and HIV infection. This scenario calls for the development of novel and more effective anti-TB drugs.

We take a multi-pronged approach to discover new anti-TB principles: i) Taking cue from Ayurveda (which mentions many plants in the treatment of tuberculosis) we select plants to find out if they possess any anti-TB molecules. Using bioactivity-guided assays we extract and purify potential anti-TB molecules. ii) Most of the anti-infectious agents, especially antibacterials, have their origin in soil bacteria and fungi. We are currently screening soil bacteria, especially actinomycetes, for their antimycobacterial activity (collaborator: Dr Sabu Thomas). In parallel we clone DNA from uncluturable bacteria into BAC vector (metagenomics) and screen the library for antimycobacterial principles (collaborator: Dr Hari Krishnan). We have demonstrated the power and utility of metagenomics by cloning a number of industrially important enzymes from environmental DNA. iii) Collaborating with scientists from other academic and research institutions across the country we screen compounds synthesized by them for their anti-TB activity.

Anti-TB screening studies are carried out on actively growing M. tuberculosis but recently we have initiated screening against dormant bacteria as well because the current drugs are not particularly effective against dormant bacteria.

Regulation of Macrophage gene expression by mycobacterial proteins.

M. tuberculosis is a facultative intracellular pathogen, which resides within the host macrophages. In intracellular pathogenic bacteria a number of virulence genes have been identified which are induced following uptake by the host. The connection between mycobacterial factors related to pathogenesis and the macrophage gene expression is not well understood. Identification and characterization of proteins involved in the signaling mechanisms, transcriptional responses, subcellular processes etc. that follow M. tuberculosis infection will greatly help understand the disease mechanism. Our laboratory aims to identify mycobacterial proteins which may be involved in regulating macrophage gene expression. Such proteins could be potential targets for antimycobacterial drug therapy.

Vitamin B₁₂ – deficiency and supplementation (Interdisciplinary program).

Vitamin B₁₂ is one of the most important cofactors needed for the hematologic, neurologic and psychological well being of all animals including humans. It plays a crucial role in the health of women especially during pregnancy and old age. Neural tube defect is one of the terrible reasons for infant mortality in India. It has been shown that Indian population is largely deficient in B₁₂. We are initiating a program to investigate the extent of deficiency of B₁₂ in our local population (collaborators: Prof MR Pillai, RGCB; Dr. Asok Antony and Dr. H. Jayaram, Indiana University) and if B₁₂ deficiency is confirmed we will supplement their food with B₁₂ and study if the deficiency can be reversed. Interestingly plants and animals do not produce B₁₂; only some bacteria can synthesize it. We have isolated certain B₁₂-producing bacteria and currently we are investigating their utility as probiotics. The possibility of transferring the B₁₂ biosynthetic pathway into common probiotics is also being explored. As an easy and vegetarian-friendly means to supplement B₁₂ we are studying whether plants can accumulate B₁₂ in various tissues (collaborator: Dr. E.V. Soniya).