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STRUCTURAL PROPERTIES OF ANTIMICROBIAL PEPTIDES ACTING ON BACTERIAL MEMBRANES. Boštjan Japelj Lek Pharmaceuticals, Drug Discovery, Ljubljana, Slovenia. Antibiotics – “miracle drugs”. Bacterial resistance is becoming a major problem in modern medicine. Cationic antimicrobial peptides:.
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STRUCTURAL PROPERTIES OF ANTIMICROBIAL PEPTIDES ACTING ON BACTERIAL MEMBRANES
Lek Pharmaceuticals, Drug Discovery, Ljubljana, Slovenia
Bacterial resistance is becoming a major problem in modern medicine
ref.: Matsuzaki, K.,. Biochim Biophys Acta, 1999. 1462(1-2): p. 1-10.
-advantage: fast acting, resistance is unlikely to develop, able to neutralize bacterial endotoxins and prevent development of sepsis
P3-55 octanoyl-FWRIRIRR– NH2
LF11 + S-LPS: trNOE
TRNOE between aromatic and aliphatic side chains in 2 mM LF11 upon addition of 1/20 of molar ratio of LPS (b) and LTA (c). The reference NOESY spectrum of LF11 is shown in (a). Spectra were recorded at a mixing time of 150 ms.
Family of 3D structures of LF11 in complex with LPS.
( basic, hydrophobic,
Complex between LF11 and LPS
441 Å2 of surface area buried
Comparison of LPS interaction motifs in FhuA (left)1, LF11 (center)2 and polymyxin B (right)3,4 in the same orientation with respect to LPS, which would be in front of the plane of the page
LF11 :Phe1 , Arg5 , Lys9 , Arg11
FhuA :Phe355, Lys439 , Arg384 , Lys351
PmxB :Phe6 , Dab8,9 , Dab3 , Dab1
1 Ferguson, A. D., Hofmann, E., Coulton, J. W., Diederichs, K., and Welte, W. (1998) Science 282:2215–2220
2Japelj, B., Pristovšek, P., Majerle, A., Jerala, R. J Biol Chem, 2005. 280(17): p. 16955-61.
3Pristovšek, P. and J. Kidrič, J Med Chem, 1999. 42(22): 4604-13
4Pristovšek, P.,Simčič, S., Wraber, B., Urleb, U. , J Med Chem, 2005. 48: 7911-7914
1 2 3 4 5 67 8 91011
F0, F…Fluorescence emission intensity in the
absence and presence of the quencher(Q)
[Q]… concentration of the quencher
KSV… Stern-Volmer quenching constant
-acylation enhances antimicrobial activity against G- and G+ bacteria
-acylation stabilizes secondary structure
CD spectra of LF11 and C12LF11 in
Family of structures of C12LF11 in DPC1
1Japelj, B., Zorko, M., Majerle, A., Pristovšek, P.,et al.. JACS, (2007), 129: 1022-1023.
OCTANOYL-F WRIRIR R – NH2
1 2 3 4 5 6 7 8 9
Structure of P3-55 in SDS
Backbone conformation of P3-55 in DPC
(NMR experiments using paramagnetic probes 5-DSA and 16-DSA)
5 - DSA
P3-55 in SDS
P3-55 in DPC
Total energy (left) and temperature (right) of the system (P3-55 + DPC + 14482 SOL + 4 Cl-) during first 2 ns of simulation
DPC + P3-55
Ratios between princpal moments of inertia of DPC during simulation of P3-55 in DPC. Principal moments of inertia are shown in the table.
*moments of inertia in units 104 amu nm2. Asymetry parameter, a, defined as a = (2I1-I2-I3)/(I1+I2+I3)
Order parameter tensor elements
of DPC micelle for the simulation
of DPC micelle a) and DPC micelle + P3-55 b). –SCD=2/3Sxx + 1/2Syy
Radial density of P3-55 in complex with DPC micelle.
DPC coordinates were taken fromTieleman, D.P., et al. J. Phys Chem. B. 2000, 104:6380-6388
Mechanism of interaction of ANEPID peptides with the membrane of Gram-negative bacteria.
Andreja Majerle, Primož Pristovšek, Mateja Zorko, Roman Jerala (NIC, Ljubljana)
Miha Kotnik, Katja Kristan, Drago Kuzman, Andrej Preželj, Jan Humljan, Petra Igličar, Vjekoslava Car, Uroš Urleb (Lek, Drug Discovery, Ljubljana)
co-workers from the EU project ANEPID (Antimicrobial Endotoxin-neutralazing
Peptides to Combat Infectious Deseases):
Dagmar Zweytick, Karl Lohner (Graz)
Guillermo Martinez de Tejada,Ignacio Moriyon, Susana Sanchez-Gomez (Pamplona)
Sylvie E. Blondelle(San Diego, CA)
Klaus Brandenburg, Jörg Andrä (Borstel)