Cell-wall interactions and the selective bacteriostatic activity of a miniature oligo-acyl-lysyl.
The oligo-acyl-lysyl, C(12(omega 7))K-beta(12), is comprised of only three Lys residues. Despite its small size, it exhibits potent bacteriostatic activity against Gram-positive bacteria, but it is approximately 10-fold less potent against Gram-negative bacteria. We followed the interactions of C(12(omega 7))K-beta(12) from its initial contact with the bacterial surface across the cell wall down to the cytoplasmic membrane. Binding to anionic lipids, as well as to negatively charged LPS and LTA, occurs with very high affinity. The C(12(omega 7))K-beta(12) does not cross the outer membrane of Gram-negative bacteria; rather, it achieves its action by depositing on the LPS layer, promoting surface adhesion and blocking passage of solutes. In Gram-positive bacteria, the thick peptidoglycan layer containing LTA allows passage of C(12(omega 7))K-beta(12) and promotes its accumulation in the small periplasm. From that location it is then driven to the membrane by strong electrostatic interactions. Despite its high potency against Gram-positive bacteria, this agent is not capable of efficiently breaking down the permeability barrier of the cytoplasmic membrane or of reaching an intracellular target, as suggested by the fact that it does not interact with DNA.
Epand
Raquel F
RF
Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. epand@mcmaster.ca
Sarig
Hadar
H
Mor
Amram
A
Epand
Richard M
RM
D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D002462:Cell Membrane / Q000737:chemistry / Q000187:drug effects; D002473:Cell Wall / Q000737:chemistry / Q000187:drug effects*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D004269:DNA, Bacterial / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004492:Edetic Acid / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000737:chemistry / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000737:chemistry; D008567:Membranes, Artificial; D008954:Models, Biological; D010457:Peptidoglycan / Q000737:chemistry / Q000187:drug effects; D019897:Periplasm / Q000737:chemistry / Q000187:drug effects; D010539:Permeability; D013211:Staphylococcus aureus / Q000737:chemistry / Q000187:drug effects*; D055672:Static Electricity; D013682:Teichoic Acids / Q000737:chemistry
D000900:Anti-Bacterial Agents; D002614:Chelating Agents; D004269:DNA, Bacterial; D004151:Dipeptides; D008070:Lipopolysaccharides; D008567:Membranes, Artificial; D010457:Peptidoglycan; D013682:Teichoic Acids; C009900:lipoteichoic acid; D004492:Edetic Acid