The National Institute of Allergy and Infectious Diseases has awarded a team of Emory researchers a five-year, $11 million dollar grant to study heteroresistance, a stealthy form of antibiotic resistance that undermines the treatment of bacterial infections.

In heteroresistance, a small subpopulation of bacterial cells display resistance to a given antibiotic. That subpopulation can be difficult to detect with conventional diagnostic tests, yet can rapidly replicate and expand when the antibiotic is applied.

“Heteroresistance is largely unappreciated and undetected in the clinic, yet it is widely prevalent and an aspect of antibiotic resistance most critical to study,” says David Weiss, PhD, associate professor of medicine (infectious diseases) at Emory University School of Medicine and director of the Emory Antibiotic Resistance Center.

Surveillance of bacteria isolated from hospitals in the United States reveals that heteroresistance to several types of antibiotics is widespread. Yet clinical diagnostic tests currently misclassify bacteria that are heteroresistant, and heteroresistance may lead to treatment failures in clinical settings. However, in this problem lies opportunity. Emory researchers have reported evidence that combining two antibiotics to which a bacterial strain exhibits heteroresistance can effectively kill bacteria that would survive otherwise.

“Our investigation of heteroresistance grew out of a collaboration between clinicians and basic scientists,” says Weiss, who is principal investigator for the grant, along with Bruce Levin, PhD, professor of biology at Emory. “In a way, we are letting the bacteria show us the most important areas to focus on.”

The new Emory funding includes several projects, and will create a “Heteroresistance Interdisciplinary Research Unit”. Two other Interdisciplinary Research Units have been funded by NIAID, including one at Baylor College of Medicine focusing on antibiotic resistance in the context of mucosal surfaces, and another at Washington University St. Louis developing new types of antibiotics.

The Emory grant’s program of research specifically focuses on heteroresistance in Enterobacteriaceae, Klebsiella and Acinetobacter baumannii, all varieties of antibiotic-resistant bacteria that the Centers for Disease Control and Prevention has named as urgent threats. Researchers will use genetics, single cell microscopy, and mathematical modeling to understand how mechanisms such as unstable gene amplification drive heteroresistance, and probe how the dynamics of bacterial cell growth affects it.

In addition to Weiss and Levin, co-investigators include Minsu Kim, PhD, Phil Rather, PhD, Jesse Jacob, MD, Eileen Burd, PhD, Sarah Satola, PhD, and project manager Amy Tunali. Dan Andersson, PhD, an expert on the genetic basis of heteroresistance from Uppsala University in Sweden, is a co-investigator on the grant.

The researchers will draw upon samples from the Clinical Microbiology Laboratory at Emory University Hospital, led by Burd, as well as the Georgia Emerging Infections Program laboratory and the recently established Investigational Clinical Microbiology Core (ICMC), part of the Antibiotic Resistance Center. The ICMC, directed by Satola. was set up for the banking and characterization of antibiotic resistant clinical isolates, environmental samples, and microbiome samples, and has a repository of bacterial isolates from more than 3500 patients, mostly from blood infections.