Heptosyltransferase I Lipid a Structure Activity Relationships (SAR)

Abstract

The increasing incidence of antibiotic resistant bacterial infections has necessitated the search for novel targets and mechanisms for therapeutic intervention. Formation of a biofilm enables survival of bacteria in hostile environments, including in the presence of antimicrobials, thereby prompting research toward the disruption of bacterial biofilms. Lipopolysaccharide (LPS), a major constituent of the outer membrane of gram-negative bacteria, plays a key role in the formation and stability of biofilms. Therefore, disrupting the biosynthesis of the LPS is an attractive mechanism for development of anti-biofilm agents. One such LPS biosynthetic enzyme is heptosyltransferase I (Hep I), which is responsible for the transfer of the first L-glycero-D-manno-heptose to a 3-deoxy-α-D-manno-oct-2-ulopyranosonic acid (KDO) of the growing Lipid A portion of LPS. Previous attempts to co-crystallize Hep I with both substrates have been unsuccessful, hindering the ability to effectively visualize the binding interactions important for specificity. Substrate analogues for E. coli Hep I Lipid A are being used to identify which portions are necessary and sufficient for binding. Determination of the SAR of Hep I for these analogues may lead to the discovery of a Lipid A analogue that is able to be co-crystallized with Hep I. Developing an understanding of E.coli Hep I binding interactions with lipid A will enhance efforts to develop a Hep I inhibitor and possibly the discovery of a new anti-biofilm agent.