Total and Semisyntheses of Polymyxin Analogues with 2‑Thr or 10-Thr Modifications to Decipher the Structure–Activity Relationship and Improve the Antibacterial Activity

Herein,
we report the total and semisyntheses of a series of polymyxin
analogues with 2-Thr and 10-Thr modifications to reveal the structure–activity
relationship (SAR), which has not been fully elucidated previously.
We employed two total-synthetic strategies to facilitate the diversified
replacements on 2-Thr or 10-Thr, respectively. Moreover, semisynthetic
approaches were utilized to achieve selective esterification of 2-Thr
or dual esterification of both 2- and 10-Thr. Based on the results
of in vitro antibacterial assays, SAR analysis implicated
that the replacement of 2-/10-Thr with amino acids carrying hydrophobic
side chains can maintain the activity against Pseudomonas
aeruginosa but had varied effects on other tested
Gram-negative bacteria. The aminoacetyl esterification on 2-/10-Thr
achieved excellent antibacterial activity, and the compound 76 exhibited 2–8-fold higher activity against different
strains and lower toxicity toward the HK-2 cell line. This work explored
the SAR of polymyxin 2-/10-Thr and provided a promising strategy for
the development of novel polymyxin derivatives.