Structurally Modified Vancomycin Demonstrates Superior Antimicrobial Activity

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A C-terminal peripheral modification of methylene pocket-modified vancomycin analog 4 results in a 200-fold increase in antimicrobial potency against vancomycin-resistant Enterococci.
A C-terminal peripheral modification of methylene pocket-modified vancomycin analog 4 results in a 200-fold increase in antimicrobial potency against vancomycin-resistant Enterococci.

Structural modifications of vancomycin improve its antimicrobial potency and durability through synergistic mechanisms of action, according to a study recently published in the Proceedings of the National Academy of Sciences (PNAS) Plus.

“A vancomycin analog that incorporates 3 structural modifications was prepared that displayed 3 independent and synergistic antimicrobial mechanisms of action,” said Dale L. Boger, PhD, Richard & Alice Cramer Professor of Chemistry and chairman of the department of chemistry at The Scripps Research Institute in La Jolla, California, in an e-mail interview with Infectious Disease Advisor

The study explored the effects of binding pocket and peripheral structural changes on vancomycin antimicrobial potency and synergistic activity. Vancomycin, a glycopeptide antibiotic, was selected for this study because antibiotics in this class successfully avoid the common mechanisms of resistance. Vancomycin confers antimicrobial action by binding to bacterial cell wall precursors and inhibiting cell wall maturation.

“The first binding pocket modification directly overcame the molecular basis of vancomycin resistance,” explained Dr Boger.

This binding pocket modification provided dual D-Ala-D-Ala/D-Ala-D-Lac binding and resulted in the formation of a methylene pocket-modified vancomycin analog 4 ([Y[CH2NH]Tpg4]vancomycin).

A C-terminal peripheral modification was then introduced to the binding pocket-modified vancomycin, inducing cell wall permeability and resulting in a 200-fold increase in antimicrobial potency against vancomycin-resistant Enterococci (VRE). Next, the investigators combined the C-terminal modification with a second peripheral (4-chlorobiphenyl)methyl (CBP) addition to the pendant disaccharide and detected even more potent antimicrobial action. The resulting analogs displayed impressive, roughly 100-fold greater, antimicrobial activity against vancomycine-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), and VRE compared with vancomycin.  

The CBP C1-aminomethylene vancomycin, a vancomycin analog with 2 complementary peripheral C1 and CBP modifications displayed especially potent antimicrobial action.

“The compound was 25,000 times more potent than vancomycin against vancomycin-resistant Enterococci and did not display a propensity for development of resistance,” said Dr Boger, and attributed this increase in antimicrobial activity to “additional mechanisms of action not found in vancomycin.” 

“Each mechanism of action enhanced antimicrobial activity potency and the durability of the antimicrobial activity toward resistance development,” added Dr Boger.

The findings of this study will likely have long-term implications in the design of potent, durable antibiotics and efforts aimed at preventing clinical antibiotic resistance. 

“The rational design of antibiotics with durable antimicrobial activity was demonstrated that promises to change the perception of possible clinical lifetimes of antibiotics,” concluded Dr Boger.  

Reference

Okano A, Isley NA, Boger, DL. Peripheral modifications of [Y[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics [published online May 30, 2017]. PNAS Plus. doi:10.1073/pnas.1704125114

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