Weaken the Barrier: Dynamic Modular Study of Lipopolysaccharide Early Transport by the Lpt Machinery

2026-07-22

Antimicrobial resistance is a global public health threat and a top priority concern in Europe with estimated 1,27 million annual deaths worldwide and 35,000 in Europe. Many of these deadly infections are caused by resistant Gram-negative bacteria which are undermining our therapeutic options because antibiotics are no longer effective. These bacteria are coated by two membranes where the one exposed to the environment is made of lipopolysaccharide—a toxic glycolipid which forms a barrier hampering the penetration of compounds, including antibiotics. These bacteria possess the Lpt multiple protein complex that bridges the two membranes and transports this essential glycolipid from the inner to the outer membrane. Target the Lpt to weaken the Gram-negative barrier, enhances antimicrobial permeability and is a viable approach to fight resistance. In this project, we will employ an interdisciplinary biophysical and computational approach to advance the currently limited knowledge of the Lpt functional mechanism, necessary for effective targeting. We will uncover how lipopolysaccharide is inserted into the machinery and squeezed out from protein to protein along the bridge. The project will integrate cutting-edge computational techniques with structural biology in a native membrane environment to bridge the knowledge gap of Lpt structure and function at the molecular level. Molecular dynamics simulations will complement Lpt cryo-EM structures by exploring the complex dynamics and regulations of the transport machinery. The project will create new research avenues to weaken the Gram-negative bacterial barrier and advance progress in Lpt-based drug discovery. Its findings will establish a knowledge framework transferable across ESKAPEs, serving as an agile resource to prevent future global outbreaks of antimicrobial resistance.

France

2026-01-01