Washington, March 15 : Researchers at Weill Cornell Medical College in New York say that the success of the lab experiments they conducted recently suggest that a new compound may provide a means to prevent active tuberculosis (TB) in people infected with the latent form of the bacterium.
The researchers say that a drug with the same properties as the compound identified by them may also help treat people who already have tuberculosis by shortening the lengthy treatment period.
They believe that their research may also pave the way for new strategies to fight bacterial infection, which is becoming increasingly resistant to traditional antibiotics.
"With each new case of antibiotic resistance, doctors are losing ground against Mycobacterium tuberculosis and other infectious diseases," said the study's senior author Dr. Carl Nathan, chairman of Microbiology and Immunology and the R.A. Rees Pritchett Professor of Microbiology at Weill Cornell Medical College.
"This new approach fights the pathogen in a way that's different from conventional antibiotics. For what may be the first time, we have found compounds that only kill M. tuberculosis when they are not dividing. This lack of replication is a characteristic of latent bacteria, which are tough to eradicate with existing antibiotics and ultimately play a huge role in the epidemic's spread," Dr. Nathan added.
An article describing the new research, published in the journal Cell Host and Microbe, suggests that, on average, each person with active TB is thought to spread infection to 9-20 other people.
"That means that killing latent M. tuberculosis is one of the keys to curtailing or eliminating TB as a disease. Antibiotic research has typically focused on killing rapidly dividing bacteria. But with antibiotic resistance rising, that no longer seems like a winning strategy. The long duration of treatment required for curing TB may reflect the fact that some of the bacteria remain non-dividing even during clinically active disease," Dr. Nathan says.
Current drug therapies take about ix months to eradicate most non-dividing bacteria. Stopping the treatment prematurely may lead to the emergence of drug-resistant bacteria that are very hard to eradicate, and may spread to other people.
The Weill Cornell experts focussed their experiments 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," said study lead author Dr. Ruslana Bryk, assistant research professor in the Department of Microbiology and Immunology at Weill Cornell Medical College.
The study on guinea pigs revealed that DlaT is crucial to triggering active TB disease, and "so we screened 15,000 compounds to find chemicals that might inhibit DlaT," said Dr. Bryk.
The researchers' efforts brought to light one such compound from a class of chemicals called rhodanines. Synthesizing over 1,000 different variants of the chemical, they found several that could enter and selectively kill non-dividing M. tuberculosis.
"We believe that these DlaT inhibitors probably target additional mechanisms that non-dividing M. tuberculosis needs to survive, and we are currently investigating that possibility. "We also believe that these compounds work in synergy with human immune responses and the chemical environment inside the host to kill latent bacteria," Dr. Nathan said.
The researcher further said that the inhibitors described in the study report are not the only ones that have 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. In recent work supported by the Bill and Melinda Gates Foundation, we have since found additional compounds that appear to kill non-dividing M. tuberculosis selectively," Dr. Nathan said.
"As a parent, a citizen and an occasional patient, I worry about losing the hard-fought gains we've made against infectious disease. When traditional antibiotics work, treating TB, pneumonia and other bacterial diseases seems routine. When they don't work -- as is happening now with growing frequency -- these infections become emergencies. The growing crisis of microbial resistance demands innovative new approaches. We hope this work will encourage more scientists that such innovations are worth seeking," Dr. Nathan added.