Shapeshifting Antibiotics: Bullvalene Linked Vancomycin Dimers are Effective Against Multidrug-Resistant Gram-Positive Bacteria

Ottonello, Alessandra, Wyllie, Jessica A, Yahiaoui, Oussama, Murray, Ewan, Williams, Paul, Bolla, Jani R, Robinson, Carol V, Fallon, Thomas, Soares da Costa, Tatiana P, Moses, John E (April 2022) Shapeshifting Antibiotics: Bullvalene Linked Vancomycin Dimers are Effective Against Multidrug-Resistant Gram-Positive Bacteria. (Submitted)

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DOI: 10.26434/chemrxiv-2022-h2pds

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 click-linked bullvalene core, hence 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, inferring 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.

Item Type: Paper
Subjects: diseases & disorders > Bacterial Infections
diseases & disorders
diseases & disorders > Bacterial Infections > Antibiotic Resistance
chemistry
chemistry > techniques > click chemistry
chemistry > techniques
CSHL Authors:
Communities: CSHL labs > Moses lab
SWORD Depositor: CSHL Elements
Depositing User: CSHL Elements
Date: 21 April 2022
Date Deposited: 03 Oct 2023 20:57
Last Modified: 16 Jan 2024 20:54
Related URLs:
URI: https://repository.cshl.edu/id/eprint/41122

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