A drug with such properties could also be useful in treating people who already have tuberculosis by shortening the lengthy treatment period. The discovery also points to new ways of thinking about fighting bacterial infection, which is becoming increasingly resistant to traditional antibiotics.
In their experiments, the Weill Cornell researchers focused on a bacterial enzyme called dihydrolipoamide acetyltransferase (DlaT). "DlaT's main job is to help M. tuberculosis get energy from nutrients. But when the bacterium is under stress, it also uses the enzyme to defend itself against oxidative damage from human immune cells, such as macrophages," explains study lead author Dr. Ruslana Bryk, assistant research professor in the Department of Microbiology and Immunology at Weill Cornell Medical College.
The team's work in guinea pigs revealed that DlaT is crucial to triggering active TB disease. "So we screened 15,000 compounds to find chemicals that might inhibit DlaT," Bryk says. The researchers discovered one such compound from a class of chemicals called rhodanines. Their collaborators at deCODE Chemistry then synthesized over 1,000 different variants until the Weill Cornell team found several that can enter and selectively kill non-dividing M. tuberculosis.
The inhibitors described in the paper are surely not the only ones with the ability to kill non-dividing M. tuberculosis selectively. "This was really a proof-of-principle effort to show that targeting non-dividing bacteria was feasible," explains Dr. Carl Nathan, chairman of Microbiology and Immunology and the R.A. Rees Pritchett Professor of Microbiology at Weill Cornell Medical College. "In recent work we have since found additional compounds that appear to kill non-dividing M. tuberculosis selectively."
“The growing crisis of microbial resistance demands innovative new approaches. We hope this work will encourage more scientists that such innovations are worth seeking", Nathan says.
MEDICA.de; Source: New York-Presbyterian Hospital