Active Tuberculosis Prevented by New Drug that Kills Latent Bacteria

A new chemical that can prevent active tuberculosis in people infected with the latent form of the bacterium has been discovered by researchers. The drug could also shorten the recovery time needed, and suggests new ways of combating bacterial infection, increasingly resistant to traditional antibiotics.

"With each new case of antibiotic resistance, doctors are losing ground against Mycobacterium tuberculosis and other infectious diseases," explains 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."
The World Health Organization reports 1.6 million worldwide die from the lung infection annually. It is also estimated that as many as one-third of the world’s population is infected with latent or non-replicating M tuberculosis. The latent bacteria begins to replicate in 5% – 10% of these people, resulting in active disease, while experts opinion states that each person with active TB is estimated to infect 9 and 20 other people.
"That means that killing latent M. tuberculosis is one of the keys to curtailing or eliminating TB as a disease," Dr. Nathan says. "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."
It can take 6 months to wipe out most non-dividing bacteria using present drugs, but if this difficult regime is stopped too early, drug-resistant bacteria can appear. The focus of the Weill Cornell researchers was 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.
DlaT is vital to initiating active TB disease, the team discovered. "So we screened 15,000 compounds to find chemicals that might inhibit DlaT," Dr. 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.
"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," Dr. Nathan says. "We also believe that these compounds work in synergy with human immune responses and the chemical environment inside the host to kill latent bacteria."
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," Dr. Nathan explains. "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."
"As a parent, a citizen and an occasional patient, I worry about losing the hard-fought gains we’ve made against infectious disease," Dr. Nathan says. "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."
The new findings are published in the March 12, 2008 online issue of the journal Cell Host & Microbe.

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