There is a rapid increase in human infections resistant to multiple antibiotics, and researchers are working hard to find ways to stem this superbug tide. Chemists in the Redinbo Group have now revealed the structure of an enzyme that helps antibiotic resistance genes to hop to new bacterial hosts - one route to superbug status. The team, published in PNAS, also describe molecules that block the enzyme's activity. Though the molecules are far from benign drugs, the authors say the strategy represents a new idea for fighting superbugs.
To pass on antibiotic-thwarting genes to a nearby microorganism, a bacterium needs an enzyme to cut one strand of its own DNA. The Redinbo Group crystallized a complex of DNA and this nicking enzyme, which they obtained from a dangerous strain of methicillin-resistant Staphylococcus aureus - MRSA - the first human pathogen to also pick up resistance to antibiotic heavy hitter vancomycin. They noticed two protein loops holding the DNA, "pinching it like a finger and a thumb," says Redinbo, arranging it for nicking. The nicked DNA strand peels off, so the bacterium can squirt it into its neighbors. Eliminating those loops from the enzyme makes Staphylococcus far less able to share DNA. The long-term goal of this work is to develop a companion therapy to traditional antibiotics that keeps resistance in check.
Findings published in Science from the Redinbo Group, in collaboration with UNC School of Medicine, the Albert Einstein College of Medicine, and North Carolina Central University, may lead to the elimination of a debilitating side effect of CPT-11, a widely used but harshly potent treatment for colon cancer. The team of researchers, led by chemistry professor Matthew Redinbo from the University of North Carolina at Chapel Hill, has discovered that it is possible to target and block the enzyme, beta glucuronidase, which is thought to play a major role in causing the drug's side effects. "In a manner of speaking, we cured the bacteria's sweet tooth without damaging the microbes or intestines and, in the process, the drug's toxic side effect was alleviated," said Redinbo.
Study co-author, Sridhar Mani, professor of medicine and genetics at Einstein, said the severe diarrhea caused by CPT-11 can sharply limit the dosage that cancer patients can receive. "Our tests showed conclusively that the inhibitor identified by our UNC colleagues prevented diarrhea in mice that were also receiving CPT-11. We are hopeful that clinical trials will show that administering this inhibitor when patients start taking CPT-11 allows for improvement in the drug's anti-tumor effect in patients with cancer."
Several bacterial pathogens require the "twitching" motility produced by filamentous type IV pili (T4P) to establish and maintain human infections. Two cytoplasmic ATPases function as an oscillatory motor that powers twitching motility via cycles of pilus extension and retraction. The regulation of this motor, however, has remained a mystery. In a collaborative work published in PNAS, members of the Redinbo Group have discovered that a single atom – a calcium, in fact – can control how bacteria walk.
By resolving the structure of a protein involved in the movement of the opportunitistic human pathogen Pseudomonas aeruginosa,the scientists identified a spot on the bacteria, that when blocked, can stop it in its tracks. The finding identifies a key step in the process by which bacteria infect their hosts, and could one day lead to new drug targets to prevent infection.
Contact: Matt Redinbo; (919) 843-8910 office; (919) 962-7576 lab