Project

Gyrase B Inhibitors for Tuberculosis

SRI is seeking new treatments for tuberculosis, a global health crisis.

a high-throughput fluorescence polarization assay

Tuberculosis, commonly known as TB, claims nearly two million lives each year.

According to the World Health Organization, two billion people—one-third of the world’s population—are infected with the TB mycobacterium. The disease may not manifest into active TB until months or even years later, and some infected individuals will not develop active TB at all. Only individuals with active TB can infect others. Treatment, which often requires multiple drugs, can last up to nine months and may cause severe side effects. Noncompliance with treatment has led to drug resistance.

SRI’s goal is to develop a new drug that is effective against drug-resistant strains of TB and shortens the treatment period by half. A treatment that can eliminate TB in less time and with fewer side effects could interrupt the transmission of this deadly disease.

SRI researchers are developing drugs that target the gyrase subunit B (GyrB) protein in Mycobacterium tuberculosis. Targeting DNA gyrase is a clinically validated therapeutic approach; fluoroquinolone antibiotics, for instance, target the gyrase subunit A (GyrA) of the functional heterotetramer. Increasing resistance to fluoroquinolones has driven interest in targeting GyrB, which has not previously been targeted for TB.

SRI has developed new potent GyrB inhibitors that kill bacteria during actively replicating and non-replicating stages. These inhibitors are active against several drug-resistant TB strains, including fluoroquinolone-resistant bacteria, and significantly reduce the lung colony-forming unit counts in a murine TB model.

Ultimately, optimized inhibitors that target GyrB could lead to improved treatment regimens for multi-drug-resistant TB infections.

The project described was supported by Award Number U01AI082070 from the National Institute of Allergy And Infectious Diseases. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy And Infectious Diseases or the National Institutes of Health.

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DNA gyrase

In research at SRI International, scientists evaluating new drug targets against tuberculosis (TB) recently validated the preclinical effectiveness of a target that could rapidly eliminate infections and potentially shorten treatment time.