Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin

• Published in: Journal of medicinal chemistry Vol. 61; no. 8; pp. 3409 - 3421
• Main Authors: Zong, Yu, Sun, Xiuyun, Gao, Hongying, Meyer, Kirsten J, Lewis, Kim, Rao, Yu
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 26.04.2018; Amer Chemical Soc
• Subjects: Animals; Anti-Bacterial Agents - chemical synthesis; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Chemistry, Medicinal; Depsipeptides - chemical synthesis; Depsipeptides - chemistry; Depsipeptides - pharmacology; Female; Hydrophobic and Hydrophilic Interactions; Life Sciences & Biomedicine; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice, Inbred C57BL; Microbial Sensitivity Tests; Molecular Structure; Pharmacology & Pharmacy; Science & Technology; Sepsis - drug therapy; Streptococcus pneumoniae - drug effects; Streptococcus pyogenes - drug effects; Structure-Activity Relationship; Uridine Diphosphate N-Acetylmuramic Acid - analogs & derivatives; Uridine Diphosphate N-Acetylmuramic Acid - antagonists & inhibitors; Uridine Diphosphate N-Acetylmuramic Acid - chemistry; Vancomycin-Resistant Enterococci - drug effects; TARGET; INFECTIONS; L-ALLO-ENDURACIDIDINE; ANTIBIOTIC-RESISTANCE; STAPHYLOCOCCUS-AUREUS MRSA; PHARMACOPHORE; INHIBITORS; RESIDUES; BINDING; CELL-WALL BIOSYNTHESIS
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.7b01241

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.