Novel lipoglycopeptides as inhibitors of bacterial signal peptidase I.
Signal peptidase (SPase) I is responsible for the cleavage of signal peptides of many secreted proteins in bacteria. Because of its unique physiological and biochemical properties, it serves as a potential target for development of novel antibacterial agents. In this study, we report the production, isolation, and structure determination of a family of structurally related novel lipoglycopeptides from a Streptomyces sp. as inhibitors of SPase I. Detailed spectroscopic analyses, including MS and NMR, revealed that these lipoglycopeptides share a common 14-membered cyclic peptide core, an acyclic tripeptide chain, and a deoxy-alpha-mannose sugar, but differ in the degree of oxidation of the N-methylphenylglycine residue and the length and branching of the fatty acyl chain. Biochemical analysis demonstrated that these peptides are potent and competitive inhibitors of SPase I with K(i) 50 to 158 nm. In addition, they showed modest antibacterial activity against a panel of pathogenic Gram-positive and Gram-negative bacteria with minimal inhibitory concentration of 8-64 microm against Streptococcus pneumonniae and 4-8 microm against Escherichia coli. Notably, they mechanistically blocked the protein secretion in whole cells as demonstrated by inhibiting beta-lactamase release from Staphylococcus aureus. Taken together, the present discovery of a family of novel lipoglycopeptides as potent inhibitors of bacterial SPase I may lead to the development of a novel class of broad-spectrum antibiotics.
Kulanthaivel
Palaniappan
P
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Kreuzman
Adam J
AJ
Strege
Mark A
MA
Belvo
Matthew D
MD
Smitka
Tim A
TA
Clemens
Matthew
M
Swartling
James R
JR
Minton
Kristina L
KL
Zheng
Feng
F
Angleton
Eddie L
EL
Mullen
Deborah
D
Jungheim
Louis N
LN
Klimkowski
Valentine J
VJ
Nicas
Thalia I
TI
Thompson
Richard C
RC
Peng
Sheng-Bin
SB
D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D004926:Escherichia coli / Q000378:metabolism; D005285:Fermentation; D005998:Glycine / Q000737:chemistry; D006020:Glycopeptides / Q000737:chemistry / Q000494:pharmacology*; D006090:Gram-Negative Bacteria / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000737:chemistry*; D008956:Models, Chemical; D010455:Peptides / Q000737:chemistry; D021382:Protein Sorting Signals; D011522:Protons; D012697:Serine Endopeptidases / Q000737:chemistry*; D021241:Spectrometry, Mass, Electrospray Ionization; D013053:Spectrophotometry; D013211:Staphylococcus aureus / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000378:metabolism; D013302:Streptomyces / Q000378:metabolism; D013997:Time Factors; D001618:beta-Lactamases / Q000378:metabolism
D006020:Glycopeptides; D008565:Membrane Proteins; D010455:Peptides; D021382:Protein Sorting Signals; D011522:Protons; D012697:Serine Endopeptidases; C026515:type I signal peptidase; D001618:beta-Lactamases; D005998:Glycine