The international research effort was led by Dr. John S. Blanchard, the Dan Danciger Professor of Biochemistry at the Albert Einstein College of Medicine. The findings are published in the June 3 issue of Science.
Fluoroquinolones, an important class of antibiotics that includes ciprofloxacin (Cipro), work against TB by interfering with the microbe's ability to reproduce itself. Specifically, the drugs target an enzyme called DNA gyrase, which helps untwist bacterial DNA during replication. However, TB has been developing resistance to fluoroquinolones due to their increasing use in treating multi-drug-resistant TB infections.
Until recently, this resistance was due entirely to mutations in DNA gyrase that prevent fluoroquinolones from binding to the complex formed by the enzyme and DNA. Now, the Science article has identified a new strategy by which TB bacteria may be able to resist fluoroquinolones--and that other microbes are already using.
After studying the three-dimensional structure of a TB protein called MfpA, the researchers found that the protein contains a fold that mimics DNA. So rather than binding with DNA--and becoming a target for the fluoroquinolones--DNA gyrase instead binds with the DNA "mimic" MfpA, rendering the fluoroquinolones ineffective. Proteins similar to MfpA are also present in Shigella, E. coli and other disease-causing bacteria that have developed fluoroquinolone resistance.
"Our study shows that this novel bacterial mechanism is responsible for the rapid spread of fluoroquinolone resistance that is making hospital-acquired infections so difficult to treat," says Dr. Blanchard.
Additional members of the research team were postdoctoral fellows Subray S. Hegde and Matthew W. Vetting, and Dr. Steven L. Roderick (Albert Einstein College of Medicine in Bronx, NY); Dr. Anthony Maxwell (The John Innes Centre in Norwich, England); and Dr. Howard E. Takiff (Instituto Venezolano de Investigaciones Cientificas in Caracas, Venezuela).
Journal
Science