(Philadelphia, PA) - In today's online early edition of the Proceedings of the National Academy of Sciences, researchers at the University of Pennsylvania School of Medicine describe how one antibiotic currently under Phase III clinical testing, ramoplanin, works on the molecular level to disrupt the ability of bacteria to build cell walls. The researchers believe that lessons learned from ramoplanin may aid in developing new classes of antibiotics for treatment of antimicrobial resistance.

"Ramoplanin is more effective than front line antibiotics such as vancomycin. In comparison to vancomycin, ramoplanin's relatively simplistic chemical architecture lends itself well to chemical synthesis and modification - qualities highly desirable for drug development," said Dewey G. McCafferty, PhD, assistant professor in Penn's Department of Biochemistry and Biophysics. "More importantly, ramoplanin dodges the problems of antibiotic resistance by attacking the bacteria in a spot that cannot be easily overcome by normal mechanisms of mutational resistance."

The ability of bacteria to acquire resistance to antibiotics stands testament to the ingenuity of evolution and, perhaps, to the overuse of bacteria-killing drugs. In a sense, antibiotics replace natural selection in driving changes in bacteria, as the survival of a single resistant cell can lead to whole new population of resistant bacteria. Distressingly, bacteria have grown resistant to vancomycin, the antibiotic of last resort for more than 30 years. Ramoplanin, however, has been found to be up to ten times as powerful as vancomycin and no resistance to the antibiotic has been reported to date.

Ramoplanin and vancomycin both attack the ability of bacteria to cross link together cell wall building blocks to form peptidoglycan, the large polymer made of sugars and amino acids that provides mechanical strength for the bacteria cell wall. Bacteria treated with ramoplanin or vancomycin form weakened cell walls that spontaneously burst, killing the cell. The difference is where the two antibiotics make their attack on peptidoglycan biosynthesis.

"Vancomycin attaches to peptidoglycan monomers at the end of the peptide chain, where two D-alanine amino acid residues are found. The genes that cause vancomycin resistance work by creating a competing peptidoglycan monomer with a mutation that reduces the ability of the antibiotic to bind. Vancomycin just bounces off the cell surface and the bacteria goes unscathed," explained McCafferty. "Ramoplanin, however, attaches itself to an essential sugar within the peptidoglycan molecule. This interaction would be much more difficult for evolutionary resistance mechanisms to overcome since it would involve making multiple changes to the normal way bacteria makes its cell wall."

Still, evolution has come up with clever solutions to seemingly intractable problems in the past. That is why McCafferty and his colleagues are exploring the mechanism of action and chemical synthesis of ramoplanin. Understanding how the antibiotic binds to peptidoglycan would allow us to build even better antibiotics. As it is, ramoplanin is substantially smaller and less complicated than conventional antibiotics, which also makes it easier to manufacture.

"Ramoplanin represents a genuinely new class of antimicrobial for the treatment of drug-resistant bacterial infections," said McCafferty. "Our discovery of the molecular basis of its action will hopefully lead to the development of smaller, simplistic drugs derived from ramoplanin's structure with better antibiotic activity or more favorable biological properties."

Funding for this research was provided by the National Institutes of Health, the American Cancer Society, and the McCabe fund.


# # #

Editor's Note:

Dr. McCafferty has no financial stake in Biosearch Italia (the patent-holder of ramoplanin) or any of its licensees.

The University of Pennsylvania Health System (UPHS) is an international leader in biomedical research, medical education and quality care. UPHS is distinguished not only by its historical significance - first hospital (1751), first medical school (1765), first university teaching hospital (1874), and first fully integrated academic health system (1993) - but also by its position as a major player on the world stage of medicine in the 21st century.


 


 

 

.

Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $6.7 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 20 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2016 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2016, Penn Medicine provided $393 million to benefit our community.

Share This Page: