Polymyxins slow down lateral diffusion of proteins and lipopolysaccharide in the E. coli outer membrane

Area of Science:

• Microbiology
• Biophysics
• Computational Biology

Background:

• Polymyxins are critical last-resort antibiotics for Gram-negative infections.
• Increasing resistance and side effects necessitate the development of alternative therapies.
• Understanding polymyxin interaction with the bacterial outer membrane is key to designing new drugs.

Purpose of the Study:

• To investigate the initial association and aggregation of polymyxins with the Gram-negative bacterial outer membrane.
• To elucidate the molecular mechanisms by which polymyxins affect outer membrane structure and dynamics.
• To provide insights into polymyxin translocation barriers for developing novel antibiotics.

Main Methods:

• Multi-scale molecular simulations were employed.
• Models of the E. coli outer membrane, including lipids and native proteins, were utilized.
• Atomistic resolution was used to analyze protein-lipopolysaccharide-polymyxin interactions.

Main Results:

• Polymyxins adsorb to the outer membrane surface, hindering lateral movement of proteins and lipopolysaccharides.
• Polymyxins form large aggregates with outer membrane proteins, linking them together.
• Detailed interaction networks between membrane components and polymyxins were identified, explaining reduced mobility.

Conclusions:

• Polymyxin binding significantly alters outer membrane dynamics by forming protein-polymyxin complexes.
• This study provides a molecular basis for polymyxin's action and potential resistance mechanisms.
• Findings inform the design of new antimicrobial agents targeting the Gram-negative outer membrane.