EpidemicsOvercoming dangerous antibiotic-resistant bacteria

A team of scientists from the Scripps Research Institute have successfully reengineered an important antibiotic to kill the deadliest antibiotic-resistant bacteria. The compound could one day be used clinically to treat patients with life-threatening and highly resistant bacterial infections.

The results were published in an advanced online issue of the Journal of the American Chemical Society.

“[These results] have true clinical significance and chart a path forward for the development of next generation antibiotics for the treatment of the most serious resistant bacterial infections,” said Dale L. Boger, who is Richard and Alice Cramer Professor of Chemistry at The Scripps Research Institute and senior author of the new study. “The result could not be predicted. It really required the preparation of the molecule and the establishment of its properties.”

A Scipps release reports that the compound synthesized is an analogue of the well-known commercial antibiotic vancomycin.

The new analogue was prepared in an elegant total synthesis, a momentous achievement from a synthetic chemistry point of view. “In addition to the elegantly designed synthesis,” said Jian Xie, postdoctoral fellow in Boger’s group and first author on the publication, “I am exceedingly gratified that our results could have the potential to be a great service to mankind.”

Vancomycin is an antibiotic of last resort, which is used only after treatment with other antibiotics has failed.

Clinically, it is used to treat patients that are either infected with the virulent methicillin-resistant Staphylococcus aureus (MRSA), individuals on dialysis, or those allergic to beta-lactam antibiotics (penicillin, cephalosporins).

The drug was first used clinically in the 1950s, and the first vancomycin-resistant bacterial strains were isolated in the 1980s.

Vancomycin normally works by grabbing hold of and sequestering the bacterial cell-wall making machinery, a peptidoglycan (carbohydrate and peptide containing molecule). Only Gram-positive bacteria have a cell wall, which is a membrane on the cell’s outer surface.

The antibiotic binds so tightly to the peptidoglycan that the bacteria can no longer use the machinery to make their cell wall and thus die.

Unfortunately, bacteria have found a way to alter the peptidoglycan in such a way that the antibiotic can no longer grab hold. Think of it as trying to hold a ball without any fingers. Biochemically the bacteria express a mutant form of the peptidoglycan in which properties of a key atom used in the recognition process are changed. This simply means where there once was something attractive there is now something repulsive. Chemically, the bacteria