Researchers at Wayne State University recently received a $2.5 million grant from the National Institute of Allergy and Infectious Diseases of the National Institutes of Health for a study that aims to shape the next generation of antibiotics for the treatment of multidrug-resistant diseases.
The project is led by David Crich, Ph.D., Schaap Professor of Organic Chemistry in the Department of Chemistry in Wayne State's College of Liberal Arts and Sciences, and is a collaboration with groups at the Institute of Medical Microbiology at the University of ZÃ¼rich, the Kresge Hearing Institute at the University of Michigan, and the USDA Agricultural Research Station in Peoria, IL. The project will study aminoglycoside antibiotics (AGAs) that have long been used as potent broad spectrum antibiotics. These antibiotics are often used to treat complex infectious diseases such as hospitalized continuous ambulatory peritoneal dialysis (CAPD) and exacerbated cystic fibrosis (CF), as well as Methicillin-resistant Staphylococcus aureus (MRSA), multidrug-resistant tuberculosis (MDR-TB) and various gram-negative pathogens.
According to Crich, current AGAs are susceptible to resistance, and have limitations due to nephrotoxicity and especially AGA-induced permanent hearing loss (ototoxicity) which occurs in up to 20 percent of the patient population. With a better understanding of the molecular basis for AGA-induced ototoxicity and resistance, Crich and his research team aim to design and synthesize novel AGAs that do not suffer from the complications of toxicity or suffer resistance.
"Together with our collaborators, we plan to evaluate the novel AGAs in vitro and in animal models for efficacy against gram-positive and gram-negative organisms and lack of ototoxicity and nephrotoxicity," said Crich. "We will screen these synthetic compounds for their ability to inhibit bacterial and eukaryotic ribosomes that are indicative of antibacterial activity and toxicity, respectively, and also look at their activity against engineered bacterial strains carrying specific types of resistance."
The team's ultimate goal will be to use the data acquired to design the next generation of compounds that will be validated and tested for reduced toxicity and decreased resistance, ultimately in the hopes for further development of the drug.
"There are many new cases of drug-resistant bacteria every year that threaten effective prevention and treatment of an ever-increasing range of infections," said Gloria Heppner, associate vice president for research at Wayne State. "Dr. Crich's work is critical in helping to solve a major global public health crisis. Without research such as his, we are facing a growing list of common infections and injuries that may soon be untreatable."
The project number for this National Institutes of Health study is AI123352.