Modified Version of Vancomycin Could Fight Antibiotic-Resistant Bacteria

May 31, 2017 by News Staff / Source

A team of researchers at the Scripps Research Institute has structurally modified vancomycin to make an already-powerful version of the antibiotic even more potent.

             This digitally-colorized scanning electron microscopic image depicts Enterococcus faecalis. Image credit: Pete Wardell / CDC.

The original form of vancomycin is an ideal starting place for developing better antibiotics.
The antibiotic has been prescribed by doctors for six decades, and bacteria are only now developing resistance to it.
             “Vancomycin was disclosed in 1956 and introduced into the clinic in 1958,” the researchers said.
“After nearly 60 years of clinical use and even with the past use of glycopeptide antibiotics for agricultural livestock (avoparcin), resistant pathogens have only slowly emerged, and vancomycin remains an integral and increasingly important antibiotic today.”
“Clinical resistance was initially observed with vancomycin-resistant Enterococci that was detected only after 30 years of clinical use but now, also includes vancomycin-resistant Staphylococcus aureus.”
Previous studies by the team had shown that it is possible to add two modifications to vancomycin to make it even more potent.
            “With these modifications, you need less of the drug to have the same effect,” said Dr. Dale Boger, Richard and Alice Cramer Professor of Chemistry at the Scripps Research Institute and senior author of the paper reporting the results in the Proceedings of the National Academy of Sciences this week.
The new study shows that scientists can make a third modification — which interferes with a bacterium’s cell wall in a new way — with promising results.
Combined with the previous modifications, this alteration gives vancomycin a 1,000-fold increase in activity, meaning doctors would need to use less of the antibiotic to fight infection.
The discovery makes this version of vancomycin — CBP C1-aminomethylene vancomycin — the first antibiotic to have three independent mechanisms of action.
            “CBP C1-aminomethylene vancomycin incorporates the redesigned pocket modification for dual d-Ala-d-Ala/d-Ala-d-Lac binding (blocks cell wall synthesis by ligand binding, including inhibition of transpeptidase-catalyzed cross-linking), the CBP disaccharide modification (blocks cell wall synthesis by direct transglycosylase inhibition without d-Ala-d-Ala/d-Ala-d-Lac binding), and the C1 quaternary ammonium salt C-terminal modification (induces membrane permeability),” the authors said.
“This compound exhibited the most potent inhibition of cell wall synthesis in the assay of all compounds assessed as well as the most pronounced and potent induced cell membrane permeability of all compounds examined.”
            “It represents an analog of vancomycin deliberately designed to overcome vancomycin resistance, which incorporates three structural modifications that impart three independent mechanisms of action.”

            Structure of CBP C1-aminomethylene vancomycin, summary of activity, and mechanisms of action. Image credit: Okano et al, doi: 10.1073/pnas.1704125114.

“This increases the durability of this antibiotic,” Dr. Boger said.
“Organisms just can’t simultaneously work to find a way around three independent mechanisms of action.      Even if they found a solution to one of those, the organisms would still be killed by the other two.”
Tested against Enterococci bacteria, CBP C1-aminomethylene vancomycin killed both vancomycin-resistant Enterococci and the original forms of Enterococci.
           “Doctors could use this modified form of vancomycin without fear of resistance emerging,” Dr. Boger said.
The next step for the team is to design a way to synthesize the modified vancomycin using fewer steps in the lab, as the current method takes 30 steps.
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Akinori Okano et al. Peripheral modifications of [Ψ[CH₂NH]Tpg⁴]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. PNAS, published online May 30, 2017; doi: 10.1073/pnas.1704125114