American Chemical Society
jm2c01915_si_002.pdf (2.85 MB)

Critical Role of Position 10 Residue in the Polymyxin Antimicrobial Activity

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journal contribution
posted on 2023-02-06, 16:39 authored by Nitin A. Patil, Wendong Ma, Xukai Jiang, Xiaoji He, Heidi H. Yu, Hasini Wickremasinghe, Jiping Wang, Philip E. Thompson, Tony Velkov, Kade D. Roberts, Jian Li
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.