17 research outputs found
Lateral membrane organization as target of an antimicrobial peptidomimetic compound
Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes.</p
Luciferin and derivatives as a DYRK selective scaffold for the design of protein kinase inhibitors
Probing the ATP binding pocket of protein kinase DYRK1A with benzothiazole fragment molecules
DYRK1A has emerged
as a potential target for therapies of Alzheimerâs
disease using small molecules. On the basis of the observation of
selective DYRK1A inhibition by firefly d-luciferin, we have
explored static and dynamic structural properties of fragment sized
variants of the benzothiazole scaffold with respect to DYRK1A using
X-ray crystallography and NMR techniques. The compounds have excellent
ligand efficiencies and show a remarkable diversity of binding modes
in dynamic equilibrium. Binding geometries are determined in part
by interactions often considered âweakâ, including âorthogonal
multipolarâ types represented by, for example, FâCO,
sulfurâaromatic, and halogenâaromatic interactions,
together with hydrogen bonds that are modulated by variation of electron
withdrawing groups. These studies show how the benzothiazole scaffold
is highly promising for the development of therapeutic DYRK1A inhibitors.
In addition, the subtleties of the binding interactions, including
dynamics, show how full structural studies are required to fully interpret
the essential physical determinants of binding
Lateral membrane organization as target of an antimicrobial peptidomimetic compound
Antimicrobial resistance is one of the leading concerns in medical care. Here we study the mechanism of action of an antimicrobial cationic tripeptide, AMC-109, by combining high speed-atomic force microscopy, molecular dynamics, fluorescence assays, and lipidomic analysis. We show that AMC-109 activity on negatively charged membranes derived from Staphylococcus aureus consists of two crucial steps. First, AMC-109 self-assembles into stable aggregates consisting of a hydrophobic core and a cationic surface, with specificity for negatively charged membranes. Second, upon incorporation into the membrane, individual peptides insert into the outer monolayer, affecting lateral membrane organization and dissolving membrane nanodomains, without forming pores. We propose that membrane domain dissolution triggered by AMC-109 may affect crucial functions such as protein sorting and cell wall synthesis. Our results indicate that the AMC-109 mode of action resembles that of the disinfectant benzalkonium chloride (BAK), but with enhanced selectivity for bacterial membranes.</p