PUBLICATION
Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles
- Authors
- Habjan, E., Lepioshkin, A., Charitou, V., Egorova, A., Kazakova, E., Ho, V.Q., Bitter, W., Makarov, V., Speer, A.
- ID
- ZDB-PUB-240515-7
- Date
- 2024
- Source
- Life science alliance 7(7): (Journal)
- Registered Authors
- Bitter, Wilbert
- Keywords
- none
- MeSH Terms
-
- Humans
- Microbial Sensitivity Tests
- Antitubercular Agents/pharmacology
- Drug Synergism*
- Benzothiazoles*/pharmacology
- Mycobacterium tuberculosis/drug effects
- Anti-Bacterial Agents/pharmacology
- Macrophages/drug effects
- Macrophages/metabolism
- Macrophages/microbiology
- Cell Membrane Permeability/drug effects
- Zebrafish*
- Mycobacterium marinum*/drug effects
- Mycobacterium Infections, Nontuberculous/drug therapy
- Mycobacterium Infections, Nontuberculous/microbiology
- Rifampin/pharmacology
- Animals
- Cell Membrane/drug effects
- Cell Membrane/metabolism
- PubMed
- 38744470 Full text @ Life Sci Alliance
Citation
Habjan, E., Lepioshkin, A., Charitou, V., Egorova, A., Kazakova, E., Ho, V.Q., Bitter, W., Makarov, V., Speer, A. (2024) Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles. Life science alliance. 7(7):.
Abstract
Developing effective tuberculosis drugs is hindered by mycobacteria's intrinsic antibiotic resistance because of their impermeable cell envelope. Using benzothiazole compounds, we aimed to increase mycobacterial cell envelope permeability and weaken the defenses of Mycobacterium marinum, serving as a model for Mycobacterium tuberculosis Initial hit, BT-08, significantly boosted ethidium bromide uptake, indicating enhanced membrane permeability. It also demonstrated efficacy in the M. marinum-zebrafish embryo infection model and M. tuberculosis-infected macrophages. Notably, BT-08 synergized with established antibiotics, including vancomycin and rifampicin. Subsequent medicinal chemistry optimization led to BT-37, a non-toxic and more potent derivative, also enhancing ethidium bromide uptake and maintaining synergy with rifampicin in infected zebrafish embryos. Mutants of M. marinum resistant to BT-37 revealed that MMAR_0407 (Rv0164) is the molecular target and that this target plays a role in the observed synergy and permeability. This study introduces novel compounds targeting a new mycobacterial vulnerability and highlights their cooperative and synergistic interactions with existing antibiotics.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping