5W18

Staphylococcus aureus ClpP in complex with (S)-N-((2R,6S,8aS,14aS,20S,23aS)-2,6-dimethyl-5,8,14,19,23-pentaoxooctadecahydro-1H,5H,14H,19H-pyrido[2,1-i]dipyrrolo[2,1-c:2',1'-l][1]oxa[4,7,10,13]tetraazacyclohexadecin-20-yl)-3-phenyl-2-(3-phenylureido)propanamide

Summary for 5W18

• Entry DOI: 10.2210/pdb5w18/pdb
• Descriptor: ATP-dependent Clp protease proteolytic subunit, 9V7-PHE-SER-PRO-YCP-ALA-MP8 (3 entities in total)
• Functional Keywords: clpp, hydrolase-antibiotic complex, udep, hydrolase/antibiotic
• Biological source: Staphylococcus aureus (strain NCTC 8325); More
• Total number of polymer chains: 28
• Total formula weight: 327173.70

Authors

Lee, R.E.,Griffith, E.C. (deposition date: 2017-06-02, release date: 2017-08-09, Last modification date: 2024-11-06)

Primary citation

Griffith, E.C.,Zhao, Y.,Singh, A.P.,Conlon, B.P.,Tangallapally, R.,Shadrick, W.R.,Liu, J.,Wallace, M.J.,Yang, L.,Elmore, J.M.,Li, Y.,Zheng, Z.,Miller, D.J.,Cheramie, M.N.,Lee, R.B.,LaFleur, M.D.,Lewis, K.,Lee, R.E.
Ureadepsipeptides as ClpP Activators.
Acs Infect Dis., 2019

PubMed 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 ClpP and show activity against Gram-positive bacteria, including 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.

PubMed: 31588734
DOI: 10.1021/acsinfecdis.9b00245

Experimental method

X-RAY DIFFRACTION (2.44 Å)