A modified version of vancomycin makes the powerful antibiotic even stronger and packs a three-way punch against resistance, a new study shows.

Akinori Okanoa, PhD, from the Department of Chemistry at the Scripps Research Institute, La Jolla, California, and colleagues have reengineered the structure of vancomycin by adding three modifications that significantly increase its potency and decrease the likelihood of resistance, the authors report in an article published online May 30 in the Proceedings of the National Academy of Sciences.

Combined, the modifications produce a 1000-fold increase in activity, which would mean physicians could use less of the antibiotic when fighting infection.

The researchers previously reported two of the three modifications. One of those modifications alters the cell wall binding pocket to directly overcome the molecular basis of vancomycin resistance. The second one is a peripheral modification that adds a new chemical to the analog to interfere with bacterial cell walls and boost the drug's activity against sensitive and resistant bacteria strains, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci.

In the current report, Dr Okanoa and colleagues describe a third peripheral modification that also interferes with bacterial cell walls, but via a different mechanism.

"[T]he changes we've made reflect three different mechanisms for attacking bacteria, making the emergence of resistance very difficult," according to senior investigator Dale Boger, PhD, cochair of the Department of Chemistry at the Scripps Research Institute.

To date, the modified antibiotic has been tested against resistant bacteria in the laboratory, where it was shown to be at least 25,000 times more potent against vancomycin-resistant enterococci and vancomycin-resistant Staphylococcus aureus, the authors write. Moreover, neither strain of bacteria acquired resistance even after 50 rounds of testing with the modified agent.

At this time, development of the synthetic antibiotic molecule is a 30-step process, which would make commercial production difficult, Dr. Boger told Medscape Medical News in an interview. "We are now focused on refining the process so that it is simpler and cost-reduced, after which we will begin preclinical testing for efficacy and safety. Our hope and goal is to have the drug clinically available within 5 years."

Although vancomycin was the target for this drug development project because of its long history of use and only recent emergence of resistance, similar approaches could be used for other antibiotics. "We hope our work inspires others to apply the approach to other classes of antibiotics, particularly as the threat of antibiotic failures increases," Dr. Boger said.

The study was supported by the National Institutes of Health. The authors have disclosed no relevant financial relationships.

Proc Natl Acad Sci. Published online May 30, 2017.Abstract

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