Pyrylium derivatives as outer membrane permeabilizers against MDR gram-negative bacteria via multi-target mode of...

Area of Science:

• Medicinal Chemistry
• Microbiology
• Drug Discovery

Background:

• Multidrug-resistant (MDR) Gram-negative bacteria pose a significant global health threat, necessitating novel therapeutic strategies.
• Existing antibiotics are becoming less effective due to resistance mechanisms in bacteria such as Acinetobacter baumannii and Escherichia coli.

Purpose of the Study:

• To synthesize and evaluate novel pyrylium derivatives as potential antibiotic adjuvants.
• To investigate the mechanism of action of promising compounds against MDR Gram-negative pathogens.

Main Methods:

• Synthesis of pyrylium derivatives based on IMB-0042.
• In vitro and in vivo evaluation of antibacterial activity and synergy with polymyxin B against Acinetobacter baumannii and Escherichia coli.
• Investigation of the mechanism of outer membrane permeabilization, including LptA/LptC interaction and lipopolysaccharide (LPS) interaction.

Main Results:

• Compound 4a demonstrated significant synergistic activity with polymyxin B against both Acinetobacter baumannii and Escherichia coli.
• Compound 4a was identified as an effective outer membrane (OM) perturbant, inhibiting LptA/LptC interaction by targeting Met47 in LptA.
• The cationic pyrylium structure reduced OM densification through electrostatic interactions with anionic lipopolysaccharide (LPS).

Conclusions:

• Pyrylium derivatives represent a novel class of multi-target outer membrane permeabilizers.
• These compounds can significantly potentiate the efficacy of existing antibiotics against MDR Gram-negative bacteria.
• The findings offer a promising new avenue for combating challenging Gram-negative infections.