PDBsum entry 6pmd

Hydrolase/antibiotic

PDB id: 6pmd

Contents

Protein chains

(+ 8 more) 184 a.a.

Ligands

SHV-WFP-SER-PRO-YCP-ALA-MP8 ×11

MPD ×14

Waters ×1167

References listed in PDB file

Key reference

• Title: Ureadepsipeptides as clpp activators.
• Authors: E.C.Griffith, Y.Zhao, A.P.Singh, B.P.Conlon, R.Tangallapally, W.R.Shadrick, J.Liu, M.J.Wallace, L.Yang, J.M.Elmore, Y.Li, Z.Zheng, D.J.Miller, M.N.Cheramie, R.B.Lee, M.D.Lafleur, K.Lewis, R.E.Lee.
• Ref.: ACS Infect Dis, 2019, 5, 1915-1925. [DOI no: 10.1021/acsinfecdis.9b00245]
• PubMed id: 31588734

Abstract

Acyldepsipeptides are a unique class of antibiotics that act via allosterically dysregulated activation of the bacterial caseinolytic protease (ClpP). The ability of ClpP activators to kill nongrowing bacteria represents a new opportunity to combat deep-seated biofilm infections. However, the acyldepsipeptide scaffold is subject to rapid metabolism. Herein, we explore alteration of the potentially metabolically reactive α,β unsaturated acyl chain. Through targeted synthesis, a new class of phenyl urea substituted depsipeptide ClpP activators with improved metabolic stability is described. The ureadepsipeptides are potent activators of Staphylococcus aureus ClpP and show activity against Gram-positive bacteria, including S. aureus biofilms. These studies demonstrate that a phenyl urea motif can successfully mimic the double bond, maintaining potency equivalent to acyldepsipeptides but with decreased metabolic liability. Although removal of the double bond from acyldepsipeptides generally has a significant negative impact on potency, structural studies revealed that the phenyl ureadepsipeptides can retain potency through the formation of a third hydrogen bond between the urea and the key Tyr63 residue in the ClpP activation domain. Ureadepsipeptides represent a new class of ClpP activators with improved drug-like properties, potent antibacterial activity, and the tractability to be further optimized.