Superdrugs for superbugs

How do you solve a problem like multi-drug resistance in disease-causing bacteria? One potential solution is to chemically modify antibiotics currently used in therapy so that they can overcome bacterial resistance mechanisms. A recent study, published in PNAS, has done just this and developed a modified ‘resistance-proof’ version of the last resort antibiotic, vancomycin(1).

Vancomycin has been in use for over 60 years for the treatment of serious enterococcal and methicillin-resistant Staphylococcus aureus (MRSA) infections. However, the past three decades has seen a decline in the clinical effectiveness of vancomycin with enterococci acquiring resistance in the 1980s, followed by MRSA in the early 2000s. Bacterial cell wall synthesis requires the cross-linking of peptidoglycan, polymers of sugar and protein, by the transpeptidase enzyme. Vancomycin interferes with this process by binding to D-alanine-D-alanine amino acid motifs on the polymers. Vancomycin-resistant bacteria can switch the terminal D-alanine of the amino acid motif with D-lactic acid. This single amino acid swap is in fact enough to decrease the potency of vancomycin by a thousand-fold.

Researchers at the Scripps Institute in California previously rescued the efficacy of vancomycin by modifying the peptidoglycan binding pocket to recognise both D-alanine-D-alanine and D-alanine-D-lactic acid motifs(2). In this study(1), they have introduced further alterations to this modified version to develop a ‘superdrug’ which is 25,000 times more potent than the original vancomycin. As the new drug targets bacterial cell wall synthesis and permeability in three independent ways, the researchers predict that there is a low likelihood of bacteria acquiring resistance against it.

If this new version of vancomycin is safe and efficacious in clinical trials it would be a welcome addition in our arms race against drug-resistant bacteria.

Publications:

1. Okano, A., Isley, N. A. and Boger, D. L. (2017) Peripheral modifications of
[Ψ[CH2NH]Tpg4]vancomycin with added synergistic mechanisms of action provide durable and potent antibiotics. PNAS, doi:10.1073/pnas.1704125114.
2. Crowley, B.M and Boger, D. L. (2006) Total Synthesis and Evaluation of [Ψ[CH2NH]Tpg4]Vancomycin Aglycon:  Reengineering Vancomycin for Dual d-Ala-d-Ala and d-Ala-d-Lac Binding. J. Am. Chem. Soc., 128 (9), 2885–2892, doi: 10.1021/ja0572912.

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Madushi_Wanaguru

Post-doctoral scientist at the Francis Crick Institute.
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