teixobactin and Sepsis

Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia.

Topics: Animals; Anti-Bacterial Agents; Depsipeptides; Female; Hydrophobic and Hydrophilic Interactions; Methicillin-Resistant Staphylococcus aureus; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Sepsis; Streptococcus pneumoniae; Streptococcus pyogenes; Structure-Activity Relationship; Uridine Diphosphate N-Acetylmuramic Acid; Vancomycin-Resistant Enterococci