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NIAID Contributes to New TB Drug With Broad Antibiotic Potential

An NIAID collaboration has resulted in a new antibiotic that shows promise against drug-susceptible and drug-resistant tuberculosis (TB) bacteria as well as other infectious agents such as fungi, nontuberculous mycobacteria (NTM), and Helicobacter pylori. The drug, called SQ-109, was discovered in 1999 by a team of NIAID researchers led by Clifton Barry III, Ph.D., and developed with grant and contract support from NIAID and contributions by the National Cancer Institute/NIAID Inter-Institute Program for the Development of AIDS-related Therapeutics. In 2006, NIH licensed the SQ-109 technology to biotech company Sequella, Inc., under a Cooperative Research and Development Agreement.

illustration of SQ-109 structure
Three-dimensional structure of SQ-109, a derivative of ethambutol with which it shares a common ethylenediamine core (the two nitrogens in blue spheres connected by two carbons in grey). Credit: NIAID

A Test Them All Approach

TB is second only to HIV/AIDS as the greatest killer worldwide due to a single infectious agent, according to the World Health Organization. It is notoriously hard to treat. TB patients must adhere to a complex treatment regimen over a 6- to 8-month period. This demanding schedule often results in patients skipping treatment doses, which has helped give rise to drug-resistant strains of M. tuberculosis, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB.

In the late 1990s, Dr. Barry and colleagues in the NIAID Laboratory of Clinical Infectious Diseases developed a sweeping "test them all" approach to find new TB drugs. They used "combinatorial chemistry" to synthesize tens of thousands of structural variants of ethambutol, a TB drug from the 1950s, and screened them for their ability to kill TB bacteria. Promising candidates were structurally varied and again screened. After testing more than 100,000 variations, researchers found that one candidate, called SQ-109, was among the best. If successful, SQ-109 will be one of the first drugs developed using combinatorial chemistry to make it to market.

SQ-109 is an oral antibiotic that could become part of a new first-line treatment regimen for TB infection. SQ-109 travels quickly to the lungs, where most TB bacteria reside. It then weakens the cell walls of the bacteria, which ultimately results in their death. Current TB drug regimens rely on four first-line drugs: isoniazid, rifampicin, pyrazinamide, and ethambutol. At the high doses where it is most effective, ethambutol is a highly toxic drug with serious side effects that include blindness and nerve damage. SQ-109 works differently than these drugs and is far less toxic than ethambutol. The reduced toxicity means that SQ-109 can be used at higher doses, raising hopes that adding SQ-109 to therapy regimens with isoniazid and rifampicin could reduce the duration of treatment and improve cure rates. SQ-109 also has the added benefit of effectively treating latent TB infection, unlike current TB drugs.

Further complicating matters, not all current TB drugs are effective against MDR and XDR TB. Drug-resistant strains of TB have severely reduced the number of drugs that can treat TB successfully. The risk of bacteria becoming resistant to even more current drugs makes developing new drugs like SQ-109 a high priority.

Partnership Accelerates Development

NIAID's collaboration with Sequella to further develop SQ-109 demonstrates the key role that public-private partnerships can play in developing new interventions to improve public health. In 2007, the drug was granted "orphan drug" status by the Food and Drug Administration and the European Medicines Agency for development against drug-susceptible and drug-resistant TB. This designation has helped accelerate clinical testing of the drug, which currently is in Phase II clinical trials. The two parties signed a Research Collaboration Agreement in 2012 to continue evaluating SQ-109 in combination with other TB drugs.

Sequella has amended its licensing agreement with the National Institutes of Health three times to pursue additional uses for SQ-109 against other infectious agents, including fungi, a variety of NTM, and H. pylori, the primary cause of gastric cancer. Researchers aim to evaluate SQ-109 as a faster-acting drug that promises to shorten the duration of treatment and counters the emergence of bacteria resistant to current antibiotics.

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Last Updated March 08, 2013