5dkp
Crystal Structure of N. meningitidis ClpP in complex with agonist ADEP A54556.Crystal Structure of N. meningitidis ClpP in complex with agonist ADEP A54556.
Structural highlights
FunctionCLPP_NEIMB Cleaves peptides in various proteins in a process that requires ATP hydrolysis. Has a chymotrypsin-like activity. Plays a major role in the degradation of misfolded proteins.[HAMAP-Rule:MF_00444] Publication Abstract from PubMedThe problem of antibiotic resistance has prompted the search for new antibiotics with novel mechanisms of action. Analogues of the A54556 cyclic acyldepsipeptides (ADEPs) represent an attractive class of antimicrobial agents that act through dysregulation of caseinolytic protease (ClpP). Previous studies have shown that ADEPs are active against Gram-positive bacteria (e.g., MRSA, VRE, PRSP (penicillin-resistant Streptococcus pneumoniae)); however, there are currently few studies examining Gram-negative bacteria. In this study, the synthesis and biological evaluation of 14 novel ADEPs against a variety of pathogenic Gram-negative and Gram-positive organisms is outlined. Optimization of the macrocyclic core residues and N-acyl side chain culminated in the development of 26, which shows potent activity against the Gram-negative species Neisseria meningitidis and Neisseria gonorrheae and improved activity against the Gram-positive organisms Staphylococcus aureus and Enterococcus faecalis in comparison with known analogues. In addition, the co-crystal structure of an ADEP-ClpP complex derived from N. meningitidis was solved. Development and Characterization of Potent Cyclic Acyldepsipeptide Analogues with Increased Antimicrobial Activity.,Goodreid JD, Janetzko J, Santa Maria JP Jr, Wong KS, Leung E, Eger BT, Bryson S, Pai EF, Gray-Owen SD, Walker S, Houry WA, Batey RA J Med Chem. 2016 Jan 28;59(2):624-46. doi: 10.1021/acs.jmedchem.5b01451. Epub, 2016 Jan 12. PMID:26818454[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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