Redox Homeostasis Modulators in TB

TB has experienced a dramatic resurgence in recent years and now infects one third of the world's population. There is a growing incidence of multi-drug resistant TB strains, caused primarily by non-compliance with current treatment regimens.

Our redox homeostasis modulators programme represents a completely novel class of drug which may have the potential either to reduce overall treatment times, thereby improving patient compliance, and /or to treat multi-drug resistant TB.

A number of our compounds have been tested for anti-TB activity at the United States NIH TAACF (National Institutes of Health Tuberculosis Antimicrobial Acquisition and Coordination Facility), with encouraging results.

PMX 464 has shown substantial in vitro activity against TB thioredoxin, producing more than 90% inhibition in a fluorescence based assay, with minimum inhibitory concentrations in the micromolar range.

We believe that the promising activity of PMX 464 in the TAACF screen may be due partly to inhibition of thioredoxin C, a key component of the most important redox cascade possessed by the M.tuberculosis bacterium.

A collaborative programme at Nottingham has generated the crystal structure of TB-thioredoxin, providing the starting point for a rational drug design programme to identify new molecules that are selective for TB-thioredoxin relative to human thioredoxin.

Structure of Mycobacterium tuberculosis thioredoxin C

World Health Organization
www.who.int

National Instititute of Allergy and Infectious Diseases
www3.niaid.nih.gov

Tuberculosis Anti-Microbial Acquisition and Co ordination Facility (TAACF)
www.taacf.org

Global Alliance on TB
new.tballiance.org