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Reviving An Antibiotic Target
Structural Biology: Novel binding interaction could lead to new class of antibacterial drugs
Carmen Drahl
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GlaxoSmithKline View Enlarged ImageCAUGHT 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 tacklingdrug-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 drugresistance, 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 focuson 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 infectiousdiseases 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 ofDNA 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 gyraseis poised to cleave DNA but has not yet done so—the first time gyrase has been captured in this configuration.

GSK299423 effectively kills a variety of drug-resistant bacteria, includingmethicillin-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...
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