A team of researchers led by Brown University infectious disease experts and engineers has identified a new class of antibiotics that could one day help combat the alarming emergence of drug-resistant “superbugs.”

Eleftherios Mylonakis, a Professor of Infectious Diseases at Brown’s Warren Alpert Medical School and Chief of Infectious Diseases at Rhode Island Hospital and the Miriam Hospital, led a multidisciplinary team of researchers searching for drugs to target bacteria that have developed a resistance to conventional antibiotics. In addition to fellow scientists at Brown, Mylonakis collaborated with researchers from Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Emory University and Northwestern University.

The research team developed novel ways to screen a remarkable 82,000 synthetic compounds to identify those that would serve as effective antibiotics but not be toxic to humans. Ultimately, 85 compounds were identified that decreased the ability of MRSA to kill laboratory roundworms. Of those, two synthetic retinoids were selected as the best candidates for further study.

The two synthetic retinoids demonstrated the ability to kill MRSA (methicillin-resistant Staphylococcus aureus), a type of staph bacteria that is resistant to several antibiotics. Retinoids, which are chemically related to Vitamin A, are used to treat a variety of health problems, including acne and cancer. The work has been described in the journal Nature.

Sophisticated computer modeling and other studies showed that these retinoids impair bacterial membranes.  Moreover, these compounds kill so-called MRSA “persister” cells that are drug-resistant dormant cells that are not susceptible to current antibiotic therapies. The ability of the drugs to make bacterial membranes more permeable also appeared to be factor in why they worked well in tandem with an existing antibiotic, gentamicin.

Chemists at Emory University, as part of the research team, modified the retinoids to retain maximum potency against MRSA, while minimizing toxicity.

The computer modeling was led by Huajian Gao, a professor in Brown’s School of Engineering and one of the study’s authors. The powerful computer simulations demonstrated a route toward understanding the molecular interactions between the screened compounds and bacteria membrane and determining the energy barriers for their penetration and embedment inside the membrane.

“This has been a very exciting multidisciplinary project,” Gao said. 

Mylonakis added, “We are extremely optimistic.” But “this is still years away from coming to clinical trial.”

The study was supported by National Institutes of Health (Grant P01 AI083214), the National Science Foundation (Grant CMMI-156290) and the National Institute of General Medical Sciences (Grant 1R35GM119426).