Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria

Ottonello, Alessandra; Wyllie, Jessica A.; Yahiaoui, Oussama; Sun, Shoujun; Koelln, Rebecca A.; Homer, Joshua A.; Johnson, Robert M.; Murray, Ewan; Williams, Paul; Bolla, Jani R.; Robinson, Carol V.; Fallon, Thomas; Soares da Costa, Tatiana P.; Moses, John E.

Abstract

The alarming rise in superbugs that are resistant to drugs of last resort, including vancomycin-resistant enterococci and staphylococci, has become a significant global health hazard. Here, we report the click chemistry synthesis of an unprecedented class of shapeshifting vancomycin dimers (SVDs) that display potent activity against bacteria that are resistant to the parent drug, including the ESKAPE pathogens, vancomycin-resistant Enterococcus (VRE), methicillin-resistant Staphylococcus aureus (MRSA), as well as vancomycin-resistant S. aureus (VRSA). The shapeshifting modality of the dimers is powered by a triazole-linked bullvalene core, exploiting the dynamic covalent rearrangements of the fluxional carbon cage and creating ligands with the capacity to inhibit bacterial cell wall biosynthesis. The new shapeshifting antibiotics are not disadvantaged by the common mechanism of vancomycin resistance resulting from the alteration of the C-terminal dipeptide with the corresponding d-Ala-d-Lac depsipeptide. Further, evidence suggests that the shapeshifting ligands destabilize the complex formed between the flippase MurJ and lipid II, implying the potential for a new mode of action for polyvalent glycopeptides. The SVDs show little propensity for acquired resistance by enterococci, suggesting that this new class of shapeshifting antibiotic will display durable antimicrobial activity not prone to rapidly acquired clinical resistance.

Citation

Ottonello, A., Wyllie, J. A., Yahiaoui, O., Sun, S., Koelln, R. A., Homer, J. A., Johnson, R. M., Murray, E., Williams, P., Bolla, J. R., Robinson, C. V., Fallon, T., Soares da Costa, T. P., & Moses, J. E. (2023). Shapeshifting bullvalene-linked vancomycin dimers as effective antibiotics against multidrug-resistant gram-positive bacteria. Proceedings of the National Academy of Sciences, 120(15), Article e2208737120. https://doi.org/10.1073/pnas.2208737120

• Journal Article Type: Article
• Acceptance Date: Feb 24, 2023
• Online Publication Date: Apr 3, 2023
• Publication Date: Apr 11, 2023
• Deposit Date: Apr 12, 2023
• Publicly Available Date: May 25, 2023
• Journal: Proceedings of the National Academy of Sciences
• Print ISSN: 0027-8424
• Electronic ISSN: 1091-6490
• Publisher: National Academy of Sciences
• Peer Reviewed: Peer Reviewed
• Volume: 120
• Issue: 15
• Article Number: e2208737120
• DOI: https://doi.org/10.1073/pnas.2208737120
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/19298173
• Publisher URL: https://www.pnas.org/doi/10.1073/pnas.2208737120