Photo-Augmented DHFR Inhibition: N-Methylbenzothiazole Derivatives against Resistant Gram ± Bacteria

Area of Science:

• Medicinal Chemistry
• Photodynamic Therapy
• Antimicrobial Resistance

Background:

• Antimicrobial resistance (AMR) is a growing global health crisis requiring new therapeutic approaches.
• Conventional antibiotics are losing efficacy against multidrug-resistant (MDR) pathogens.
• Novel strategies combining different mechanisms are needed to combat resistant bacteria.

Purpose of the Study:

• To design and develop novel D-π-A conjugated benzothiazole derivatives.
• To investigate their synergistic antibacterial activity through DHFR inhibition and photodynamic therapy (PDT).
• To evaluate their efficacy against MDR pathogens and in a preclinical wound infection model.

Main Methods:

• Rational design and synthesis of benzothiazole derivatives.
• Structure-activity relationship (SAR) studies to identify lead compounds.
• In vitro antibacterial assays against Gram-positive and Gram-negative strains.
• Photodynamic activation studies measuring ROS generation and antimicrobial enhancement.
• In vivo efficacy evaluation in a MRSA-infected murine wound model.

Main Results:

• Compound 12, a benzothiazole derivative, exhibited potent intrinsic antibacterial activity exceeding that of linezolid and vancomycin.
• Photodynamic activation of compound 12 increased its antimicrobial efficacy up to 64-fold via ROS generation.
• In vivo studies showed complete bacterial eradication and significant wound healing with compound 12 and PDT.

Conclusions:

• Novel benzothiazole derivatives offer a promising dual-action therapeutic strategy against MDR pathogens.
• The combination of DHFR inhibition and PDT presents a viable approach to overcome antimicrobial resistance.
• Compound 12 demonstrates significant potential for clinical development in treating resistant bacterial infections.