Selectivity Modulation and Structure of α/aza‐β³ Cyclic Antimicrobial Peptides

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 structure of cyclic α/aza-β -pseudopeptides is described for the first time. Interestingly, such scaffolds are stabilized by successive inverse γ- and N-N turns (hydrazino turns), a unique feature due to the aza-β residues. The α-amino acid side chains form a cluster on one face of the ring, while the aza-β -amino acid side chains are projected around the ring in the equatorial orientation. Such structural data are particularly valuable to fine-tune the bioactivity of these ACPPs by a structure-based approach.

The Mechanisms of Action of Cationic Antimicrobial Peptides Refined by Novel Concepts from Biophysical Investigations

“…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.…”

Biophysical Investigations Elucidating the Mechanisms of Action of Antimicrobial Peptides and Their Synergism

“…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.…”

Novel antibiotics effective against gram-positive and -negative multi-resistant bacteria with limited resistance

“…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).…”