Earlier this month, President Barack Obama announced a five-year plan to solve the growing problem of antibiotic resistance. Researchers now report structural modifications to the antibiotic vancomycin that could help. They believe the modified drug would be difficult for bacteria to evade.
The natural product vancomycin has been in clinical use for decades and has long been considered an antibiotic of last resort against antibiotic-resistant bacteria, including methicillin-resistant Staphylococcus aureus, a cause of hospital-acquired infections. But bacteria have increasingly developed resistance to it. Researchers have been searching for new antibiotics to take its place, but success has been limited.
Vancomycin kills bacteria by disrupting bacterial cell-wall biosynthesis. Bacteria develop resistance to it by substituting an amino acid in a cell-wall component, preventing vancomycin from binding. Dale L. Boger and coworkers at Scripps Research Institute in La Jolla, Calif., earlier designed and synthesized an amidine analog of vancomycin that restored binding to the modified cell-wall component. It showed activity against vancomycin-resistant and -sensitive bacteria, but it was less than a home run.
They now report a chlorobiphenyl (CBP) derivative of amidine vancomycin that hits the ball out of the park: It has 10 to 100 times the potency of native vancomycin against vancomycin-resistant and -sensitive bacteria (J. Am. Chem. Soc. 2014, DOI: 10.1021/ja507009a). Strong experimental evidence indicates that the boost is caused by a second mechanism of action granted by the CBP group, though Boger’s group and others have not yet fully characterized that mechanism.
The proposed dual mechanism turns vancomycin into a sort of cocktail that bacteria might have extraordinary difficulty resisting, Boger says, noting that it might grant the drug “another durable 50 years of clinical use.”
In a tour de force synthesis of the amidine-CBP vancomycin, Boger and coworkers created a version of the amidine vancomycin that lacks vancomycin’s two sugars, added the sugars by sequential enzymatic glycosylations, and then added the CBP group by reductive amination. The researchers hope to boost the synthesis’s yield so the compound can be entered into preclinical animal studies and subsequent clinical testing.
“This is brilliant work that reveals the combined impact of a profound mechanism-based hypothesis and incredible acumen in complex molecule synthesis to test the ideas,” synthetic chemist Scott J. Miller of Yale University says. “The arrival at the two key analogs and achieving their inhibition of cell-wall biosynthesis by two likely different mechanisms” are epic results that will inspire further work in the field, he says.