Thursday, February 26, 2015

Drug-resistant TB may be treatable with new small molecule drug

In a new study, scientists report how a new small molecule
drug appears able to kill drug-resistant tuberculosis without
toxic side effects.

Tuberculosis - known as TB - is an infection caused by the
bacterium Mycobacterium tuberculosis. TB can spread to any organ in the body, but is most commonly found in the lungs.

According to the World Health Organization (WHO), 9 million
people around the world fell ill with TB in 2013 and 1.5 million
died of it.

Although TB is curable and preventable, the threat from drug- resistant forms of the bacterium is a growing global health concern.

Improper use of antibiotics has led to new strains of TB that
are resistant to the two most powerful drugs used to treat it:
isoniazid and rifampicin.

Now, researchers at the University of Georgia (UGA) in
Athens have developed a new small molecule drug that may
serve as a treatment against multidrug-resistant TB that cannot be cured with conventional drugs.

The team reports the findings in the journal Bioorganic and
Medicinal Chemistry Letters.

Drug 'disrupts fundamental steps in reproduction process' of TB bacteria

Lead author Dr. Vasu Nair, director of the Center for Drug
Discovery at UGA, says: Fast facts about TB

• TB is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent

• About one third of the world's population has latent TB - that is, they carry the bacterium but
are not (yet) ill and so cannot pass it on

• In 2013, an estimated 480, 000 people developed multidrug-resistant TB.

"Multidrug-resistant TB is spreading rapidly in many parts of the world. There is a tremendous need for new
therapies, and we think our laboratory has developed a
strong candidate that disrupts fundamental steps in the
bacterium's reproduction process."

Like many living organisms, the processes that keep bacteria
cells like M. tuberculosis alive and functioning rely on three
types of large molecule: DNA, RNA and proteins.

Put simply, DNA is the long-term storage place for the
instructions that make the organism and all its cells and
functions. RNA molecules - which are synthesized from DNA as needed - translate requisite parts of DNA to make proteins,
the workhorses of cells.

Dr. Nair and colleagues were interested in one particular
molecule - an enzyme that helps to produce TB RNA called RNA polymerase, or RNAP. Without this molecule, the TB bacterium cannot produce the proteins it needs to survive.

The team developed a compound that interrupts the process
through which RNAP produces TB RNA. The compound - which they refer to as "Compound 2" in their paper - is a small
molecule that binds to specific amino acids and magnesium in
the bacterial cells.

Drug has 'dual-purpose therapy' potential against both TB and HIV

Dr. Nair says the compound stops M. tuberculosis bacteria from growing and reproducing, thus rendering it incapable of
spreading infection. He adds:
He and his colleagues also carried out extensive tests on human cells and cell parts to find out how long it might take for the compound to clear from the human body. Dr. Nair says the results were very favorable, and:
"The half-life is a little over 14 hours, and all traces of the drug are expected to be cleared through normal bodily functions."

The team was also surprised - when carrying out early tests on
the new compound - that it shows strong anti-HIV properties.

This could open the door to dual-purpose therapies, where the drug tackles more than one disease at the same time.

A dual-purpose drug that tackles TB and HIV at the same time is a very exciting prospect because the risk of developing TB is 26-31 times higher in people infected with HIV, according to the WHO.

UGA has a technology licensing office that is now looking for
commercial partners to help develop the drug.

A grant from the National Institutes of Health funded the study.

In October 2014, Medical News Today learned that TB is more widespread than previously thought. A drive to improve data collection on TB exposed nearly half a million more cases than had been previously estimated, the WHO said in their Global Tuberculosis Report 2014.