Critical Role of Position 10 Residue in the Polymyxin Antimicrobial Activity

Polymyxins
(polymyxin B and colistin) are lipopeptide antibiotics
used as a last-line treatment for life-threatening multidrug-resistant
(MDR) Gram-negative bacterial infections. Unfortunately, their clinical
use has been affected by dose-limiting toxicity and increasing resistance.
Structure–activity (SAR) and structure–toxicity (STR)
relationships are paramount for the development of safer polymyxins,
albeit very little is known about the role of the conserved position
10 threonine (Thr) residue in the polymyxin core scaffold. Here, we
synthesized 30 novel analogues of polymyxin B1 modified
explicitly at position 10 and examined the antimicrobial activity
against Gram-negative bacteria and in vivo toxicity
and performed molecular dynamics simulations with bacterial outer
membranes. For the first time, this study revealed the stereochemical
requirements and role of the β-hydroxy side chain in promoting
the correctly folded conformation of the polymyxin that drives outer
membrane penetration and antibacterial activity. These findings provide
essential information for developing safer and more efficacious new-generation
polymyxin antibiotics.