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Novel discovery may lead to new ways to combat TB

7 September 2017

An innovative approach for combatting multi-drug-resistant tuberculosis (TB) is being pioneered by an international team of researchers led by Maurice Wilkins Centre principal investigator Professor Greg Cook and his colleague Dr Kiel Hards at the University of Otago. 

In their recently published study in the journal PNAS, the team reported a promising approach of identifying key molecular components of Mycobacterium tuberculosis that supersensitise the pathogen to new TB drugs and enable their effectiveness to be enhanced.

TB a leading cause of death globally

According to the World Health Organization, TB is one of the top 10 causes of death globally and a leading killer of people with HIV. Around the world, 1.8 million people died of TB in 2015, with 10.4 million new cases reported. Of these new cases, it is estimated that 580,000 were multidrug-resistant.

Multi- and extensively-drug-resistant TB strains are becoming an enormous problem, with some of the world’s most vulnerable populations bearing the highest burden, says Professor Cook. Cure rates for patients with drug-resistant strains of TB are extremely low (5 to 10 per cent) and associated mortality rate very high. 

“Our team is trying to develop new ways to treat this horrible disease, because our existing weapons against it are increasingly failing, too toxic and act too slowly. Finding new drugs is an incredibly difficult proposition, with only two new drugs licensed for TB in decades,” Professor Cook says.

“We believe the key to beating TB is to discover what the key components of its physiology are that make this pathogen so stubborn to treatment by many TB drugs. During the course of his PhD work at Otago, Dr Kiel Hards uncovered respiration as an essential component in allowing TB to avoid the action of new TB drugs.

New Zealand, Singapore and US collaboration

Professor Cook and his team have been working with collaborators at Nanyang Technological University in Singapore and Albert Einstein College of Medicine in the US to investigate the key respiratory components that sensitise TB to new and old TB drugs.

“By knocking out the two respiratory oxidases of TB simultaneously – one through gene deletion and other through drug inhibition, this led to rapid cell death of drug-tolerant TB (persisters) and cleared its infection in mice,” explains Professor Cook.

“We do not yet know how it might work in humans, but this work clearly highlights the incredible potential of targeting the respiration of TB with drugs that take out both respiratory oxidases. We think that it presents an excellent avenue to develop fast-acting drugs that synergise with current TB medicines and could ultimate revolutionise the way we treat TB infections.”

Discovery could solve the multi-drug resistance problem

Current TB treatment options are typically lengthy and often unpleasant. Patients often need to take drugs for many months and these drugs can become ineffective as bacteria develop resistance to them.

“With our fresh approach to interfering with the pathogen’s respiration, we are confident that new treatments that bypass the multiple-drug resistance problem, and cut back the existing long treatment period, will not be that far around the corner,” says Professor Cook.

TB is a major focus of the Maurice Wilkins Centre’s Infectious Disease research programme.

 

"Mechanism-based inactivator of isocitrate lyases 1 and 2 from Mycobacterium tuberculosis" T. V. Pham, A.S. Murkin, M.M. Moynihan, L. Harris, P.C. Tyler, N. Shetty, J.C. Sacchettini, H.L. Huang, T.D. Meek. Proc Natl Acad Sci U S A., 2017, 114 (29): 7617-7622.