Acinetobacter baumannii, Neisseria meningitidis), it is essential in many clinically important GNB such as Pseudomonas aeruginosa, a common and potentially life-threatening nosocomial pathogen that is naturally resistant to many antibiotics 1– 6. Although LPS appears dispensable in some pathogens (e.g. The outer leaflet of this membrane consists primarily of lipopolysaccharide (LPS) 2. Infections caused by antibiotic-resistant Gram-negative bacteria (GNB) are particularly intractable due to the presence of the outer membrane that protects the bacterial cell from harsh environments and antibiotics 1. Taken together, the novel small molecule ligands and their crystal structures provide new chemical scaffolds for ligand discovery targeting lipid A biosynthesis, while revealing structural features of interest for future investigation of LpxD function.Īntibiotic resistance is a worldwide threat that challenges our ability to successfully treat bacterial infection, exhausting health care resources and worsening patient prognosis. These ligand-dependent conformational changes suggest a potential allosteric influence of reaction intermediates on ACP binding, and vice versa. In addition, ligand binding in the LpxD active site resulted in conformational changes in the distal C-terminal helix-bundle, which forms extensive contacts with acyl carrier protein (ACP) during catalysis. The new structures reveal a previously uncharacterized magnesium ion residing at the core of the LpxD trimer.
Binding poses were determined for select compounds by X-ray crystallography. aeruginosa LpxA and LpxD, including dual-binding ligands. We report the discovery of multiple small molecule ligands that bind to P. The unique structural similarities between these two enzymes make them suitable targets for dual-binding inhibitors, a characteristic that would decrease the likelihood of mutational resistance and increase cell-based activity. LpxA and LpxD are the first and third enzymes in this pathway respectively, and are regarded as promising antibiotic targets. The lipid A biosynthesis pathway is essential in Pseudomonas aeruginosa.
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