Combating Bacterial Drug Resistance via Dual-Mechanism Drive Penetration and Triple-Approach Metabolic Disruption

Area of Science:

• Antimicrobial drug development
• Photodynamic therapy
• Bacterial resistance mechanisms

Background:

• Multidrug-resistant (MDR) bacteria present a significant global health challenge.
• Overcoming bacterial physical barriers like lipopolysaccharide (LPS) and extracellular polymeric substances (EPS) while preventing resistance is difficult.
• Current treatments struggle to effectively combat MDR bacterial infections and biofilms.

Purpose of the Study:

• To develop a novel photosensitizer (PS) capable of penetrating bacterial barriers and overcoming multidrug resistance.
• To investigate the mechanisms by which the PS disrupts bacterial integrity and metabolism.
• To evaluate the efficacy of the PS-mediated photodynamic therapy (PDT) in a preclinical model.

Main Methods:

• Development of a biotin-conjugated cationic photosensitizer (ACR-DM-Bio).
• Assessment of ACR-DM-Bio's binding and uptake mechanisms via electrostatic interactions and biotin transport.
• Investigation of metabolic interference, including biotin-dependent pathways, fatty acid biosynthesis, and the tricarboxylic acid (TCA) cycle.
• Evaluation of ACR-DM-Bio-mediated PDT in a murine biofilm infection model.

Main Results:

• ACR-DM-Bio demonstrated dual mechanisms for penetrating bacterial barriers and destroying the outer membrane.
• The PS competitively disrupted biotin metabolism and inhibited fatty acid biosynthesis, compromising membrane integrity.
• Metabolic interference with the TCA cycle severely disrupted bacterial energy metabolism.
• ACR-DM-Bio-mediated PDT completely cleared biofilms and promoted tissue repair in vivo.
• ACR-DM-Bio outperformed the antibiotic polymyxin B in the murine model.

Conclusions:

• ACR-DM-Bio offers a promising strategy for treating MDR bacterial infections by combining membrane penetration and metabolic disruption.
• The developed PS effectively overcomes bacterial resistance evolution and prevents biofilm recurrence.
• This study provides a theoretical framework for designing next-generation antimicrobial photosensitizers.