When a harmful bacterium breaks down, it calls Triple A, or more specifically, RecA.

Scott Singleton, PhD Associate Professor Division of Medicinal Chemistry and Natural Products Research Interests Bio-organic and Biophysical Chemical Investigations of the Mechanisms of DNA Repair, Directed Evolution of Novel Enzymes, Development of Alternate Strategies for Targeting Drug-Resistant Pathogenic Microorganisms

Scott Singleton, a researcher at the UNC School of Pharmacy, is working to ensure that there’s no one there to answer the call.

“This research could make our current antibiotics more effective or even result in an entirely new class of antibiotic,” Singleton says.

Wrecking the DNA Repair Shop
An infection worsens as the bacteria that cause it multiply and spread. To reproduce, a bacterium must duplicate its DNA, and in this process, errors occur approximately one-third of the time, bringing the entire process to a halt until a “repairman” can get there.

That repairman is the enzyme RecA, which all bacteria need to reproduce. Singleton likens the shape of RecA to a fist giving a thumbs-up. The RecA molecules link up with “thumb” in “fist,” forming a loose chain that wraps around the DNA strand in a right-handed helix like a spring. Adenosine triphosphate gives the spring the energy to expand and stretch the DNA molecule, giving the relatively rigid double-helix structure the flexibility it needs to repair itself by shuffling base pairs around.

Singleton’s work focuses on ways to suppress RecA. He hopes to create a drug that would cause bacteria to become RecA deficient, opening up a number of therapeutic possibilities.

“By suppressing the action of RecA—either by targeting the ATP binding sites so the enzyme has no energy to carry out repairs or by plugging the “thumb hole” needed to form the chain with a peptide (a short length of protein)—we could drastically slow bacterial reproduction,” Singleton says.

Vast Potential
Singleton’s research could create a new class of antibiotics or make bacteria more susceptible to existing antibiotics, allowing patients to take much lower doses of powerful drugs such as mytomycin, a genotoxin that damages human as well as bacterial DNA. Drugs of this type are currently treatments of last resort because they can be as dangerous to the patient as they are to the bacteria.

Most exciting to Singleton is the potential to suppress a bacterial population’s ability to develop drug resistance. When under attack by medicines and on the brink of destruction, bacteria initiates what is known as the “SOS response,” mutating themselves in a desperate gamble to survive. Without RecA, which initiates and controls the SOS response, the bacteria would be out of options and unable to develop resistance to antibiotics.