Antimicrobial Conjugated Oligoelectrolytes Containing Triphenylphosphonium Solubilizing Groups

Area of Science:

• Medicinal Chemistry
• Antimicrobial Agents
• Drug Discovery

Background:

• Conjugated oligoelectrolytes (COEs) are amphiphilic antimicrobial compounds with tunable structures.
• Developing new antimicrobials is crucial to combat rising antimicrobial resistance.
• Triphenylphosphonium (TPP) groups are explored for their potential to enhance antimicrobial efficacy.

Purpose of the Study:

• To design and synthesize novel COE derivatives incorporating TPP groups.
• To evaluate the impact of TPP groups on antimicrobial activity against challenging pathogens.
• To investigate the mechanism of action and in vivo efficacy of the most potent TPP-COE.

Main Methods:

• Synthesis of COE derivatives with stilbene-conjugated segments and TPP pendant groups.
• In vitro antimicrobial susceptibility testing against ESKAPE pathogens and mycobacteria.
• Membrane interaction studies and bacterial resistance development assays.
• In vivo efficacy evaluation in a methicillin-resistant Staphylococcus aureus (MRSA) wound model.

Main Results:

• Synthesized COEs demonstrated broad-spectrum activity against multi-drug resistant (MDR) bacteria and mycobacteria.
• TPP-containing COEs exhibited enhanced activity against Gram-negative bacteria compared to ammonium analogues.
• The lead compound DM6P increased bacterial membrane permeability without significant resistance development.
• DM6P achieved 99.99% bacterial elimination in an in vivo MRSA wound model.

Conclusions:

• TPP-functionalized COEs represent a promising class of antimicrobial agents.
• This chemical strategy enhances the activity spectrum of membrane-active COE antibiotics.
• These findings offer a potential solution for tackling difficult-to-treat drug-resistant bacterial infections.