A project by the Hutchinson Center's Dr. Gerald Smith to find new antibiotics to treat TB and to simultaneously limit the evolution of resistance to antibiotics was selected for funding by the Bill & Melinda Gates Foundation Grand Challenges in Global Health. The $100,000, one-year grant was one of 81 awarded by the organization worldwide in early May.
Many TB-causing bacteria are resistant to existing antibiotics and difficult to kill. The Smith Lab will seek inhibitors of a bacterial enzyme crucial for DNA repair and mutation to resistance. These molecules are potential antibiotics, rendering bacteria more susceptible to natural defense mechanisms.
“Our objective is to develop a new class of antimicrobial drugs against Mycobacterium tuberculosis that will provide a novel means to simultaneously combat bacterial infections and block the molecular mechanisms that give rise to antibiotic resistance,” Smith said. “Such a drug will kill bacteria and block the evolution of drug resistance during treatment. Drug-resistance is one of the major problems in treating bacterial infections.”
According to Smith’s project proposal, proteins that repair broken DNA by recombination, specifically the RecBCD and AddAB nuclease-helicase enzymes, are ideal targets for this class of agents because these proteins are also required for the induction of mutagenic DNA damage repair. This type of repair generates mutations that cause resistance to antibiotics. These proteins are required for the major bacterial pathway of DNA repair and are widely distributed in bacteria but are apparently absent from eukaryotes. Furthermore, they are specifically required during infection by several diverse bacterial pathogens. With Hutchinson Center investigator Dr. Nina Salama, Smith’s lab has shown that the AddAB enzyme of Helicobacter pylori, which can cause stomach cancer, is required for efficient colonization of the stomachs of mice.
M. tuberculosis (Mtb) is an excellent test case for this proposal. Mtb has caused more deaths than any other single organism; treatment relies on antibiotic therapy but multiple-drug resistance is a major therapeutic and public health problem. In Mtb, drug resistance occurs when point mutations alter the target of antimicrobial agents. Smith’s proposed antibiotics may limit resistance to these existing agents, too.
