Abstract:Potent and selective antimicrobial cyclic pseudopeptides (ACPPs) mixing α- and aza-β -amino acids were developed. Cyclopseudopeptide sequences were designed to investigate the impact of some intrinsic molecular parameters on their biological activities. Fine changes in the nature of the side chains strongly modulated the selectivity of the ACPPs with regard to hemolysis versus antimicrobial activity. The conformational preference of such compounds in various media was extensively studied, and the typical struc… Show more
“…Whereas molecules whose interactions are with proteinaceous receptors can be made inefficient by one or a few changes in amino acid sequence, polypeptides that act by disrupting the lipid bilayer physicochemical properties are less likely to become inactivated by resistance (Rollins-Smith et al 2002). Indeed the amphipathic nature of AMPs has been found essential and can be achieved by helical (Sansom 1991;Bechinger 1997), cyclic (Cao et al 2018Laurencin et al 2018;Tsutsumi et al 2018;Zhao et al 2018), and/or β-sheet arrangements (Hong and Su 2011; Rautenbach et al 2016a, b;Sychev et al 2017;Usachev et al 2017). Thus the insights gained from the studies of cationic amphipathic antimicrobial peptides have stimulated the design of a number of small amphipathic molecules (Arnusch et al 2012;Ghosh et al 2014), pseudopeptides (Porter et al 2002;Patch and Barron 2003;Kuroda and DeGrado 2005;Violette et al 2006;Makovitzki et al 2008;Scott et al 2008;Rotem and Mor 2009;Palermo and Kuroda 2010;Laurencin et al 2018), and polymers (Rank et al 2017) with potent antimicrobial properties.…”
Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept
“…Whereas molecules whose interactions are with proteinaceous receptors can be made inefficient by one or a few changes in amino acid sequence, polypeptides that act by disrupting the lipid bilayer physicochemical properties are less likely to become inactivated by resistance (Rollins-Smith et al 2002). Indeed the amphipathic nature of AMPs has been found essential and can be achieved by helical (Sansom 1991;Bechinger 1997), cyclic (Cao et al 2018Laurencin et al 2018;Tsutsumi et al 2018;Zhao et al 2018), and/or β-sheet arrangements (Hong and Su 2011; Rautenbach et al 2016a, b;Sychev et al 2017;Usachev et al 2017). Thus the insights gained from the studies of cationic amphipathic antimicrobial peptides have stimulated the design of a number of small amphipathic molecules (Arnusch et al 2012;Ghosh et al 2014), pseudopeptides (Porter et al 2002;Patch and Barron 2003;Kuroda and DeGrado 2005;Violette et al 2006;Makovitzki et al 2008;Scott et al 2008;Rotem and Mor 2009;Palermo and Kuroda 2010;Laurencin et al 2018), and polymers (Rank et al 2017) with potent antimicrobial properties.…”
Even 30 years after the discovery of magainins, biophysical and structural investigations on how these peptides interact with membranes can still bear surprises and add new interesting detail to how these peptides exert their antimicrobial action. Early on, using oriented solid-state NMR spectroscopy, it was found that the amphipathic helices formed by magainins are active when being oriented parallel to the membrane surface. More recent investigations indicate that this in-planar alignment is also found when PGLa and magainin in combination exert synergistic pore-forming activities, where studies on the mechanism of synergistic interaction are ongoing. In a related manner, the investigation of dimeric antimicrobial peptide sequences has become an interesting topic of research which bears promise to refine our views how antimicrobial action occurs. The molecular shape concept has been introduced to explain the effects of lipids and peptides on membrane morphology, locally and globally, and in particular of cationic amphipathic helices that partition into the membrane interface. This concept has been extended in this review to include more recent ideas on soft membranes that can adapt to external stimuli including membrane-disruptive molecules. In this manner, the lipids can change their shape in the presence of low peptide concentrations, thereby maintaining the bilayer properties. At higher peptide concentrations, phase transitions occur which lead to the formation of pores and membrane lytic processes. In the context of the molecular shape concept, the properties of lipopeptides, including surfactins, are shortly presented, and comparisons with the hydrophobic alamethicin sequence are made. Keywords (separated by "-") Magainin-PGLa-Cecropin-LL37-Surfacting alamethicin-Membrane topology-Membrane pore-Membrane macroscopic phase-SMART model-Carpet model-Toroidal pore-Peptide-lipid interactions-Molecular shape concept
“…In contrast, molecules that specifically target proteinaceous receptors can be made inefficient by mutagenesis of one or a few sites, and it is much less likely that bacteria develop resistance to compounds whose primary target is the destruction of the physico-chemical properties of the lipid membrane [ 15 ]. Membrane-active peptides exhibit a wide range of structural features some being helical in their bilayer-associated state [ 16 , 17 ], others forming cyclic [ 18 , 19 , 20 , 21 ] and/or β-sheet arrangements [ 22 , 23 , 24 , 25 , 26 ]. Indeed, following the insights gained from the studies of cationic amphipathic antimicrobial peptides a number of small amphipathic molecules [ 27 , 28 ], pseudopeptides [ 21 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ], and polymers [ 37 ] have been designed and investigated, and found to also exhibit potent antimicrobial activities.…”
Biophysical and structural investigations are presented with a focus on the membrane lipid interactions of cationic linear antibiotic peptides such as magainin, PGLa, LL37, and melittin. Observations made with these peptides are distinct as seen from data obtained with the hydrophobic peptide alamethicin. The cationic amphipathic peptides predominantly adopt membrane alignments parallel to the bilayer surface; thus the distribution of polar and non-polar side chains of the amphipathic helices mirror the environmental changes at the membrane interface. Such a membrane partitioning of an amphipathic helix has been shown to cause considerable disruptions in the lipid packing arrangements, transient openings at low peptide concentration, and membrane disintegration at higher peptide-to-lipid ratios. The manifold supramolecular arrangements adopted by lipids and peptides are represented by the ‘soft membranes adapt and respond, also transiently’ (SMART) model. Whereas molecular dynamics simulations provide atomistic views on lipid membranes in the presence of antimicrobial peptides, the biophysical investigations reveal interesting details on a molecular and supramolecular level, and recent microscopic imaging experiments delineate interesting sequences of events when bacterial cells are exposed to such peptides. Finally, biophysical studies that aim to reveal the mechanisms of synergistic interactions of magainin 2 and PGLa are presented, including unpublished isothermal titration calorimetry (ITC), circular dichroism (CD) and dynamic light scattering (DLS) measurements that suggest that the peptides are involved in liposome agglutination by mediating intermembrane interactions. A number of structural events are presented in schematic models that relate to the antimicrobial and synergistic mechanism of amphipathic peptides when they are aligned parallel to the membrane surface.
“…aureus MDR clinical isolates). All 4 pseudopeptides showed bactericidal effects against all the tested clinical isolates, but 3 of them (Pep15, Pep16, and Pep19) contained aza-β3-amino acid analogs that enhance antimicrobial activity (S1 Fig) [10,11]. Indeed, higher bactericidal activity was observed for the 3 macromolecules containing amino acid analogs compared to the molecule containing only natural amino acids (Pep18).…”
Antibiotics are a medical wonder, but an increasing frequency of resistance among most human pathogens is rendering them ineffective. If this trend continues, the consequences for public health and for the general community could be catastrophic. The current clinical pipeline, however, is very limited and is dominated by derivatives of established classes, the “me too” compounds. Here, we have exploited our recent identification of a bacterial toxin to transform it into antibiotics active on multidrug-resistant (MDR) gram-positive and -negative bacterial pathogens. We generated a new family of peptidomimetics—cyclic heptapseudopeptides—inspired from a natural bacterial peptide. Out of the 4 peptides studied, 2 are effective against methicillin-resistant
Staphylococcus aureus
(MRSA) in mild and severe sepsis mouse models without exhibiting toxicity on human erythrocytes and kidney cells, zebrafish embryos, and mice. These new compounds are safe at their active doses and above, without nephrotoxicity. Efficacy was also demonstrated against
Pseudomonas aeruginosa
and MRSA in a mouse skin infection model. Importantly, these compounds did not result in resistance after serial passages for 2 weeks and 4 or 6 days’ exposure in mice. Activity of heptapseudopeptides was explained by the ability of unnatural amino acids to strengthen dynamic association with bacterial lipid bilayers and to induce membrane permeability, leading to bacterial death. Based on structure determination, we showed that cationic domains surrounded by an extended hydrophobic core could improve bactericidal activity. Because 2 peptide analogs, Pep 16 and Pep19, are effective against both MRSA and
P
.
aeruginosa
in severe sepsis and skin infection models, respectively, we believe that these peptidomimetics are promising lead candidates for drug development. We have identified potential therapeutic agents that can provide alternative treatments against antimicrobial resistance. Because the compounds are potential leads for therapeutic development, the next step is to start phase I clinical trials.
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