Modulating mycobacterial envelope integrity for antibiotic synergy with benzothiazoles

Area of Science:

• Microbiology
• Medicinal Chemistry
• Drug Discovery

Background:

• Mycobacteria possess an impermeable cell envelope, contributing to intrinsic antibiotic resistance.
• Developing new tuberculosis drugs is challenging due to this resistance mechanism.

Purpose of the Study:

• To develop novel benzothiazole compounds that increase mycobacterial cell envelope permeability.
• To identify new therapeutic strategies against Mycobacterium tuberculosis by targeting cell envelope defenses.

Main Methods:

• Screening of benzothiazole compounds for their ability to enhance membrane permeability (ethidium bromide uptake).
• Testing compound efficacy in Mycobacterium marinum-zebrafish embryo and Mycobacterium tuberculosis-infected macrophage models.
• Investigating drug synergy with existing antibiotics like vancomycin and rifampicin.
• Identifying the molecular target of lead compounds through resistance mutant analysis.

Main Results:

• The initial compound BT-08 enhanced membrane permeability and showed efficacy in infection models.
• BT-08 demonstrated synergistic effects with vancomycin and rifampicin.
• Optimized compound BT-37 exhibited improved potency and non-toxicity, maintaining synergy with rifampicin.
• MMAR_0407 (Rv0164) was identified as the molecular target of BT-37, crucial for its activity and synergy.

Conclusions:

• Novel benzothiazole derivatives (BT-08, BT-37) effectively increase mycobacterial cell envelope permeability.
• These compounds exhibit synergistic activity with existing antibiotics, offering a potential strategy to overcome drug resistance.
• Identification of MMAR_0407 as a novel drug target provides new avenues for tuberculosis treatment development.