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August 9, 2010

Reviving An Antibiotic Target

Structural Biology: Novel binding interaction could lead to new class of antibacterial drugs

Carmen Drahl

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CAUGHT IN THE ACT: GSK299423 (yellow) catches DNA gyrase as it's about to cleave DNA. GlaxoSmithKline View Enlarged Image
CAUGHT IN THE ACT GSK299423 (yellow) catches DNA gyrase as it's about to cleave DNA.

A new angle on an old molecular target could point the way to a fresh class of agents for tackling drug-resistant bacteria, a study suggests (Nature, DOI: 10.1038/nature09197). The study also sheds new light on the way in which the target, a bacterial enzyme, works.

Despite the looming threat of drug resistance, only two new classes of antibiotics have been introduced in the past 40 years. In addition to searching for new antibiotic drug targets, a team of researchers from GlaxoSmithKline decided to focus on an established one—bacterial DNA gyrase, also known as type IIA topoisomerase.

This enzyme is critical in bacteria, where it cuts and reseals DNA to regulate a variety of important tasks. Quinolone antibiotics, which target the gyrase, have been available since 1962, but drug resistance to quinolones is on the rise.

Now, the GSK team, led by Michael N. Gwynn of the company's infectious diseases research group, has found an antibiotic, dubbed GSK299423, that works against DNA gyrase in an entirely new way and could therefore exemplify a new class of antibiotics.

X-ray crystallography of DNA gyrase interacting with a substrate fragment (a small DNA double helix) and GSK299423 revealed that the agent binds at a different site than quinolone drugs do. In the X-ray structure, the gyrase is poised to cleave DNA but has not yet done so—the first time gyrase has been captured in this configuration.

GSK299423

GSK299423 effectively kills a variety of drug-resistant bacteria, including methicillin-resistant Staphylococcus aureus and quinolone-resistant pathogens. The drug blocks DNA gyrase, "even in bacteria already resistant to other antibiotics that work against this same enzyme," Gwynn said in a press release.

GSK plans to start testing an optimized compound from the new class in humans within a couple of years, according to Director of R&D Communications Melinda Stubbee. The company has carried out its studies on GSK299423 in collaboration with the Wellcome Trust's Seeding Drug Discovery Initiative and the Department of Defense Threat Reduction Agency.

C&ENtral Science

Read more on this topic over at The Haystack:

Platensimycin On My Mind

"In the mid-1990s, when genomic sequences were coming out and the lab folks were checking genes for their functions, it became clear that there were many potential targets for antibiotics," says Shahriar Mobashery, a University of Notre Dame chemist who specializes in antibiotics. Such genomics data have yet to lead to a cornucopia of new drugs, he says. However, the GSK study shows that "the old targets for antibiotics are still good, and they should not have been ignored in the past 15 years or so."

"It is reassuring to see that pharmaceutical companies are still discovering new molecules that have potential as antibacterials," says Anthony Maxwell, a gyrase expert at the John Innes Centre, in Norwich, England. "But it remains to be seen whether GSK299423 and its analogs will make it through the tortuous path to the clinic," he adds.

Chemical & Engineering News
ISSN 0009-2347
Copyright © 2011 American Chemical Society
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