Chemical highlight supporting the Lipid A role in efficient biological adaptation of Gram-negative bacteria face to external stresses

Azza Troudi (1, 2, 3, 4) , Jean Marie Pagès (1, 2, 3) , Jean Michel Brunel (1, 2, 3)

1 MCT - Membranes et cibles thérapeutiques
2 Service de Santé des Armées
3 TMCD2 - Transporteurs membranaires, chimioresistance et drug-design
4 University of Tunis El Manar

The outer membrane (OM) of Gram-negative bacteria provides an efficient barrier against external noxious compounds such as antimicrobial agents. Associated with drug target modification it contributes to the overall failure of chemotherapy. In the complex OM architecture, Lipid A plays an essential role by anchoring the lipopolysaccharide in the membrane and ensuring the spatial organization between lipids, proteins, and sugars. Currently, the targets of almost all antibiotics are intracellularly located and required for translocation across membranes. We report herein an integrated view of Lipid A synthesis, membrane assembly, a structure comparison at the molecular structure level of numerous Gram-negative bacterial species as well as its recent use as a target for original antibacterial molecules. This review paves the way for a new vision of a key membrane component that acts during bacterial adaptation to environmental stresses and for the development of new weapons against microbial resistance to usual antibiotics.

Domaines: Maladies infectieuses

Azza Troudi, Jean Marie Pagès, Jean Michel Brunel. Chemical highlight supporting the Lipid A role in efficient biological adaptation of Gram-negative bacteria face to external stresses. Journal of Medicinal Chemistry, 2021, 64 (4), pp.1816-1834. ⟨10.1021/acs.jmedchem.0c02185⟩. ⟨hal-03368186⟩