Exploration of vanoxerine analogues as antibacterial agents

Alexander D. H. Kingdon; Holly V. Adcock; Eleni-Marina Kasimati; Philip Craven; Willem van Schaik; Liam R. Cox; Gurdyal S. Besra

doi:10.1038/s41429-024-00781-9

Exploration of vanoxerine analogues as antibacterial agents

Alexander D. H. Kingdon^*
, Holly V. Adcock
, Eleni-Marina Kasimati
, Philip Craven
, Willem van Schaik
, Liam R. Cox
, Gurdyal S. Besra^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.

Original language	English
Pages (from-to)	54-63
Number of pages	10
Journal	The Journal of antibiotics
Volume	78
Issue number	1
Early online date	15 Oct 2024
DOIs	https://doi.org/10.1038/s41429-024-00781-9
Publication status	Published - Jan 2025

Bibliographical note

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Anti-Bacterial Agents/pharmacology
Microbial Sensitivity Tests
Mycobacterium tuberculosis/drug effects
Humans
Enterococcus/drug effects
Membrane Potentials/drug effects
Antitubercular Agents/pharmacology
Structure-Activity Relationship
Mycobacterium/drug effects

Access to Document

10.1038/s41429-024-00781-9Licence: Creative Commons: Attribution (CC BY)

KingdonA2024ExplorationFinal published version, 1.62 MBLicence: Creative Commons: Attribution (CC BY)

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways
Besra, D. (Principal Investigator), Bhatt, A. (Co-Investigator), Futterer, K. (Co-Investigator), Alderwick, L. (Co-Investigator) & Zhang, J. (Co-Investigator)
Medical Research Council
1/03/19 → 28/02/25
Project: Research Councils
MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery
Besra, D. (Principal Investigator), Cox, L. (Co-Investigator) & Futterer, K. (Co-Investigator)
Medical Research Council
1/04/18 → 31/03/22
Project: Research Councils

Cite this

@article{db3cf1814f6549bb9c53473abbd0ade8,

title = "Exploration of vanoxerine analogues as antibacterial agents",

abstract = "Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.",

keywords = "Anti-Bacterial Agents/pharmacology, Microbial Sensitivity Tests, Mycobacterium tuberculosis/drug effects, Humans, Enterococcus/drug effects, Membrane Potentials/drug effects, Antitubercular Agents/pharmacology, Structure-Activity Relationship, Mycobacterium/drug effects",

author = "Kingdon, \{Alexander D. H.\} and Adcock, \{Holly V.\} and Eleni-Marina Kasimati and Philip Craven and \{van Schaik\}, Willem and Cox, \{Liam R.\} and Besra, \{Gurdyal S.\}",

note = "{\textcopyright} 2024. The Author(s).",

year = "2025",

month = jan,

doi = "10.1038/s41429-024-00781-9",

language = "English",

volume = "78",

pages = "54--63",

journal = "The Journal of antibiotics",

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number = "1",

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T1 - Exploration of vanoxerine analogues as antibacterial agents

AU - Kingdon, Alexander D. H.

AU - Adcock, Holly V.

AU - Kasimati, Eleni-Marina

AU - Craven, Philip

AU - van Schaik, Willem

AU - Cox, Liam R.

AU - Besra, Gurdyal S.

PY - 2025/1

Y1 - 2025/1

N2 - Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.

AB - Mycobacterium tuberculosis is a bacterial pathogen, responsible for approximately 1.3 million deaths in 2022 through tuberculosis infections. The complex treatment regimen required to treat tuberculosis and growing rates of drug resistance, necessitates the development of new anti-mycobacterial agents. One approach is to repurpose drugs from other clinical applications. Vanoxerine (GBR 12909) was previously shown to have anti-mycobacterial activity, through dissipating the membrane electric potential and hence, cellular energetics. Several vanoxerine analogues were synthesised in this study, which exhibited a range of activities against mycobacteria and enterococcus. All active analogues had similar impacts on the membrane electric potential and inhibition of ethidium bromide efflux. The most active compound displayed reduced inhibitory activity against the known human target of vanoxerine, the dopamine transporter. This work has identified a promising analogue, which could provide a starting point for further medicinal chemistry and drug development efforts to target mycobacteria.

KW - Anti-Bacterial Agents/pharmacology

KW - Microbial Sensitivity Tests

KW - Mycobacterium tuberculosis/drug effects

KW - Humans

KW - Enterococcus/drug effects

KW - Membrane Potentials/drug effects

KW - Antitubercular Agents/pharmacology

KW - Structure-Activity Relationship

KW - Mycobacterium/drug effects

U2 - 10.1038/s41429-024-00781-9

DO - 10.1038/s41429-024-00781-9

M3 - Article

C2 - 39402358

SN - 0021-8820

VL - 78

SP - 54

EP - 63

JO - The Journal of antibiotics

JF - The Journal of antibiotics

IS - 1

ER -

Exploration of vanoxerine analogues as antibacterial agents

Abstract

Bibliographical note

UN SDGs

Keywords

Access to Document

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Projects

The Mycobacterium tuberculosis Cell Envelope: unravelling complex cell wall assembly, degradation and re-cycling pathways

MICA: Addressing the burgeoning problem of tuberculosis: Exploiting phenotypic hits to identify new protein targets for drug discovery

Cite this