Study Identifies New Class of Antibiotics

An infectious disease researcher and physician at Lifespan is the senior author of a study just published in Nature about the discovery of a new class of antibiotics that could one day help combat the alarming emergence of drug-resistant superbugs.

Eleftherios Mylonakis, chief of infectious diseases at Lifespan affiliates Rhode Island Hospital and the Miriam Hospital in Providence, and Charles C.J. Carpenter Professor of Infectious Disease at Alpert Medical School of Brown University led a multidisciplinary team of researchers searching for drugs to target bacteria that have developed a resistance to conventional antibiotics. Their pioneering methods and discovery of a new synthetic class of antibiotics is the subject of a paper published online in Nature this week.

Their research led to the identification of two synthetic retinoids, both of which 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.

"This is an emergency," Mylonakis said, citing a World Health Organization (WHO) projection that "by 2050, superbugs will surpass cancer as the global No. 1 killer. This is a frightening situation. It affects more than individuals in the hospital or the very ill or the very old. It effects everybody."

Mylonakis collaborated on the study with researchers from Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital, Brown University, Emory University and Northwestern University. He said that teams like his are stepping in to fill a void left by the major pharmaceutical companies, which for a variety of reasons have not invested in the development of new antibiotics for many years.

"In a simplistic way it’s a math problem," said Mylonakis. "It takes the bugs an average of two years to develop resistance to antibiotics. It takes more than 10 to 15 years of work to get an antibiotic into clinical practice."

Mylonakis said drug-resistant staphylococcus is of great concern for several reasons: it’s omnipresent in the environment and on our skin, is highly virulent, and can cause serious blood, bone and organ infections.

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, 185 compounds were identified that decreased the ability of MRSA to kill laboratory roundworms. Of those, two, both synthetic retinoids, were selected as the best candidates for further study. One of the original compounds and a completely novel, more active derivative were effective when tested on a mouse thigh infected with MRSA.

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 a 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 molecule weakens the cell membranes of bacteria, but human cells also have membranes,” says William Wuest, associate professor of chemistry and a member of the Emory Antibiotic Resistance Center. “We found a way to tweak the molecule so that it now selectively targets bacteria.”

The computer modeling was led by Huajian Gao, the Walter H. Annenberg Professor of Engineering at Brown University and one of the study's authors. The powerful computer simulations demonstrated a powerful 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,” said Gao.

Dr. Frederick Ausubel, study co-author and professor of genetics at Harvard Medical School and Massachusetts General Hospital said, “The development of new classes of anti-microbial compounds will be critical for combating the ever increasing incidence of antibiotic-resistant infections."

"The results were extremely positive. We are extremely optimistic," said Mylonakis. But, he added, "This is still years away from coming to clinical trial.”

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

Source: Rhode Island Hospital