Promising New Destination for Tuberculosis Treatment – ScienceDaily



Mycobacterium tuberculosis (Mtb), the tough species of bacteria that causes tuberculosis (TB), has an unexpected vulnerability that future drugs may be able to exploit, according to a study by researchers at Weill Cornell Medicine.

The researchers, whose results were published on November 15 in. appeared Nature communication, investigated the role of a Mtb enzyme that has never been extensively studied before and discovered that it is critical in breaking down available fatty acids from Mtb to provide energy and molecular building blocks for growth and survival. Deleting only that one enzyme they EtfD. calledMTB, made Mtb unable to endure infection in mice.

“This enzyme is an attractive target for tuberculosis – if silenced, the bacterium not only starves to death, but also has an additional toxic effect on it,” said lead author Dr. Sabine Ehrt, Professor of Microbiology and Immunology at Weill Cornell Medicine.

The new findings come from an observation by the first author Dr. Tiago Beites, an instructor in the Ehrt laboratory. Dr. Beites analyzed Mtb proteins and found that two of them were strikingly similar to human metabolic enzymes called ETF-α and ETF-β. The latter are known to be involved in the metabolism of fatty acids and their mutation can cause metabolic diseases.

Dr. Beites and colleagues investigated further and eventually found that the two Mtb proteins that they contain in EtfA. renamed,MTB and EtfBMTB, together form an enzyme that works with another Mtb enzyme called EtfD. calledMTBto perform a similar metabolic function for Mtb – specifically a breakdown-related process called beta-oxidation of fatty acids.

Although it was believed that fatty acid metabolism in Mtb is covered by a variety of redundant enzymes, making this set of pathways a poor drug target, the team found that the three-component complex they discovered is critical to the normal growth and survival of Mtb. A mutated Mtb without EtfDMTB – the most promising target of the three drugs as it has no human counterpart – was unable to stimulate its growth with fatty acids or related cholesterol. It was also directly damaged by a toxic effect from the build-up of long-chain fatty acids and could not detect any long-term infection in mice.

“This is a good first indication that blocking this enzyme would be an effective way to treat TB,” said Dr. Beites.

Even now in the age of antibiotics, Mtb remains a major public health threat. It is estimated that nearly a quarter of the human population is infected at the same time, mainly in South and Southeast Asia, China and parts of Africa. It also kills around 1.5 million people annually – more than any other pathogen, except for the past two years, SARS-CoV-2, the cause of COVID-19.

Mtb has been difficult to fight because it grows slowly and can hide from the immune system within the immune system itself – especially in large immune cells called macrophages that devour themselves

But then Mtb cannot destroy it. Curing Mtb infection with antibiotics is possible, but requires lengthy treatment plans that patients often fail to adhere to.

With around 4,000 genes in its genome, Mtb also has an impressive ability to develop treatment resistance. Multi-resistant Mtb strains have become a major medical problem in many parts of the world and have created an urgent need for drugs that kill this pathogen through new mechanisms.

There is evidence to suggest that fatty acid metabolism is targeted. Last year, a separate team of researchers in Europe reported that certain chemical compounds called dioxobenzo-pyrido-indoles can kill Mtb by inhibiting the enzyme that Dr. Beites and Dr. Honor EtfD. to nameMTB. The researchers at Weill Cornell Medicine have begun exploring the functions of EtfD. to enlightenMTB, therefore hope to work with the European team to further test these connections.

The researchers are also planning additional studies to see if EtfDMTB or closely related enzymes could be good targets for drugs in other disease-causing bacteria.



Comments are closed.