PROTECTOR Computational experiments suggest that MfpA (top right) binds in the "saddle" of DNA gyrase (gray and gold), the same place where DNA binds this enzyme (left).
	MATTHEW VETTING/ALBERT EINSTEIN COLLEGE OF MEDICINE

Fluoroquinolones, particularly moxifloxacin and gatifloxacin, are becoming increasingly important in the fight against TB, especially against strains that are resistant to multiple antibiotics. These drugs kill bacteria by interfering with DNA gyrase, a DNA-binding enzyme that prevents the bacterium's genomic DNA from becoming tangled during replication. Fluoroquinolones bind to the DNA-bound gyrase and prevent the enzyme from doing its work.

But resistance to these important antibiotics is on the rise, notes David C. Hooper, an infectious diseases expert at Massachusetts General Hospital. So far, nearly all fluoroquinolone-resistant M. tuberculosis strains outsmart fluoroquinolones by just one mechanism: They can make a modified DNA gyrase that isn't susceptible to the antibiotics.

Recently, fluoroquinolone resistance also has been observed in other disease-causing bacteria, including Shigella and Escherichia coli. Instead of making a modified DNA gyrase, however, these bacteria produce a small protein that protects DNA gyrase from inhibition by fluoroquinolone. Such strains are worrisome because the genetic instructions for making the protective protein are contained in a DNA plasmid that can be passed rapidly from one bacterium to another, notes John S. Blanchard of Albert Einstein College of Medicine. One such protective protein, dubbed Qnr, "has been appearing in lots of clinical strains of fluoroquinolone-resistant bacteria," Blanchard tells C&EN.

M. tuberculosis bacteria make a similar protective protein, named MfpA, according to Blanchard. He, Subray S. Hedge, Matthew W. Vetting, and coworkers now report that MfpA bears a striking resemblance to DNA. The finding "was completely unexpected," Blanchard says.

The team's 2.0-Å-resolution picture of MfpA shows that the dimeric protein folds into a right-handed helix, with extensive hydrogen-bonding interactions between the peptide backbone atoms of adjacent square-shaped coils. The protein's overall size, shape, and charge distribution closely mimic that of normal B-form DNA.

The similarity to DNA has led Blanchard's team to suggest that MfpA and its relatives interact directly with DNA gyrase. They demonstrate that MfpA fits nicely into the enzyme's DNA-binding site. Blanchard suggests that, in the presence of MfpA, DNA gyrase does not form the DNA-bound gyrase complex that is the fluoroquinolone target, rendering the drug useless.

This novel mechanism may be responsible for the rapid spread of fluoroquinolone resistance that's making multi-drug-resistant bacterial infections so difficult to treat, Blanchard says. The new structure also suggests that the sequence of MfpA could be tweaked to design DNA mimics that specifically target other DNA-binding proteins. Such designer DNA mimics could find use as therapeutics for tuberculosis and other diseases that can be treated by blocking the replication machinery, he proposes.