Bangalore: After four decades of letdown in the quest of new drugs for tuberculosis, a disease that claims two million lives a year (at least 350,000 in India, according to the government), researchers are reporting a whole new class of broad-spectrum antibiotics which they claim can be a bulwark against TB and other bacterial infections.
Reporting in Friday’s issue of the journal Cell, a team of researchers from Howard Hughes Medical Institute and Rutgers University in New Jersey says the discovery holds promise at a time when 25% of all deaths worldwide are due to bacterial infectious diseases with most disease causing bacteria turning resistant to available antibiotics.
Also See India’s Vulnerability To TB (Graphic)
Researchers have discovered three new antibiotic compounds—myxopyronin, corallopyronin and ripostatin—which are, in fact, natural products of the bacteria themselves, used by them in some sort of a chemical warfare for survival of the fittest. All three compounds block the action of RNA polymerase, particularly in bacteria. RNA polymerase is an essential enzyme in all organisms and plays a crucial role in the assembly of proteins.
This is indeed a significant development, says Tanjore Balganesh, head of research, AstraZeneca India Pvt. Ltd, in Bangalore. “Even though RNA polymerase has been recognized as a more than perfect target for drug development based on its essentiality and structural conservation across different bacteria, no synthetic inhibitors of the enzyme have emerged as lead compounds,” he adds.
Among big pharma, AstraZeneca is one of the few companies to have a dedicated TB research programme.
Balganesh thinks the excitement in the current findings is also because the suggested mode of action here has been exploited in HIV drug research. For the New Jersey researchers, “it’s an amazing site, a drug designer’s dream”.
Agrees Balganesh: “The structural data indeed suggest that it is a pocket which can accommodate multiple chemicals…it clearly is a good starting point for drug design”.
Though RNA polymerase is also the seat of action for the current TB drug rifamycins, the new compounds act through a different mechanism and researchers believe bacteria won’t turn resistant to it.
Another claim from the team comes in reducing the treatment time which currently ranges from six months to two years and is the leading cause of non-compliance and drug resistance. “The Holy Grail in TB therapy is to reduce the course of therapy from six months to two weeks, to make treatment of TB like any other bacterial infections,” says Richard Ebright of Howard Hughes.
But according to Balganesh, this claim is presumptuous. “What therapy translates to a reduction in the duration of treatment is a ‘black box’ both in terms of the properties of the compound as well as the target/pathway the compound is active (on),” he argues. This, he says, can be determined only in studies with patients.
If new drugs haven’t emerged due to big pharma’s apathy, new generation diagnostics have proved equally elusive: nothing new has arrived in 100 years. However, hope lurks in the work done by Seyed E. Hasnain, vice-chancellor, University of Hyderabad, (formerly at Centre for DNA Fingerprinting and Diagnostics) and his team.
They’ve found three new biomarkers (antigens) which show properties to detect types of TB that are beyond detection in existing diagnostics. “There is currently no way to diagnose cases of active TB but one of our antigens, PE 25, exactly discriminates active TB from other categories of the disease,” says Hasnain.
The second antigen can detect relapse cases of TB, for which no test exists today even though the drug regime in relapsed cases could be different from previous treatments. The third antigen is able to detect TB in a BCG (TB vaccine) background. That is, current tests show TB positivity even if one has had BCG vaccination and hence one is not sure if it is actual TB or a false positive due to background BCG, explains Hasnain, who has licensed his work to California-based life sciences company Biogenics.
Though these antigens are potential biomarkers for diagnostics, more specific and accurate than existing ones, but they have been tested in a small population. “We are working with Biogenics to validate the results in a larger well-defined population,” says Sharmistha Banerjee, a team member.
Her group believes a cost-effective and user-friendly diagnostics could emerge from this as it is an ELISA-based system, which was the first screening test to be commonly used for HIV.
New drug or diagnostics— whichever comes first will speed up TB’s race against time, particularly when it’s the global non-profit alliance that is driving research, not the big pharma.