Development of an Activity Assay for Discovery of Inhibitors of Lipopolysaccharide Transport

摘要

Antibiotic-resistant Gram-negative infections are a serious health threat. Unlike Gram-positive bacteria, Gram-negative organisms have an outer membrane (OM) that restricts access to many antibiotics that might otherwise be useful. This membrane contains an outer leaflet composed of lipopolysaccharide (LPS), which creates a hydrophilic barrier that prevents easy passage of small hydrophobic molecules (Figure 1). Because improper synthesis, transport, or assembly creates a defective (leaky) OM, it has been suggested that inhibitors of LPS biogenesis could be useful antibiotics, either alone or in combination with known antibiotics. Indeed, inhibitors of LpxC, the enzyme that catalyzes the first committed step in LPS biosynthesis, have shown promise as antibacterial agents.