New Drug Candidate Destroys Non-Replicating Tuberculosis Bacteria

Destroying disease-causing bacteria when they are in a latent state is a major challenge for microbiologists and clinicians. A recently published paper described the identification of a potential drug that kills the latent form of Mycobaterium tuberculosis, the bacteria that causes TB.

About a third of the world's population may be infected with latent or non-replicating M. tuberculosis. In about 5 to 10% of these individuals, the latent bacteria eventually begin to replicate, causing active disease. On average, each person with active TB is thought to spread the infection to between 9 and 20 other people

Investigators at Weill Cornell Medical College (New York, NY, USA; www.med.cornell.edu) screened over 15,000 compounds to find chemicals that might inhibit the enzyme dihydrolipoamide acyltransferase (DlaT) that is used by M. tuberculosis to obtain energy from nutrients and act as a defense mechanism against oxidative damage from human immune cells, such as macrophages.

Results published in the March 13, 2008, online edition of the journal Cell Host & Microbe revealed that some rhodanine compounds could almost exclusively kill non-replicating mycobacteria in synergy with products of host immunity, such as nitric oxide and hypoxia, and were effective on bacteria within macrophages, a cellular reservoir for latent M. tuberculosis.

"With each new case of antibiotic resistance, doctors are losing ground against Mycobacterium tuberculosis and other infectious diseases,” explained senior author Dr. Carl Nathan, 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. 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.”


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