Structure-Interaction Relationship of Polymyxins with Lung Surfactant

Area of Science:

• Microbiology
• Biochemistry
• Pharmacology

Background:

• Multidrug-resistant Gram-negative bacteria pose a significant global health threat.
• Polymyxins are last-resort antibiotics but have poor efficacy in pulmonary infections.
• Alveolar lung surfactant is implicated in reduced polymyxin effectiveness.

Purpose of the Study:

• To investigate how alveolar lung surfactant affects polymyxin antibacterial activity.
• To elucidate the interaction mechanisms between polymyxins and lung surfactant.
• To develop novel polymyxin analogs with improved efficacy against Gram-negative lung infections.

Main Methods:

• Integrated chemical biology approaches.
• Molecular dynamics simulations.
• Structure-interaction relationship analysis.
• Thermodynamic elucidation of polymyxin penetration through surfactant barriers.

Main Results:

• Lung surfactant acts as a phospholipid-based permeability barrier, reducing polymyxin efficacy.
• Detailed structure-interaction and thermodynamic data of polymyxin-surfactant interactions were obtained.
• A novel polymyxin analog, FADDI-235, demonstrated potent activity against Gram-negative bacteria, irrespective of lung surfactant presence.

Conclusions:

• Lung surfactant sequesters polymyxins, compromising their activity against Gram-negative bacteria.
• Understanding these interactions is crucial for overcoming antibiotic resistance in pulmonary infections.
• Findings facilitate the rational design of next-generation lipopeptide antibiotics for treating Gram-negative bacterial pneumonia.