Abstract
Previous optimisation studies of peptide/peptoid hybrids typically comprise comparison of structurally related analogues displaying different oligomer length and diverse side chains. The present work concerns a systematically constructed series of 16 closely related 12-mer oligomers with an alternating cationic/hydrophobic design, representing a wide range of hydrophobicity and differences in relative side-chain lengths. The aim was to explore and rationalise the structure–activity relationships within a subclass of oligomers displaying variation of three structural features: (i) cationic side-chain length, (ii) hydrophobic side-chain length, and (iii) type of residue that is of a flexible peptoid nature. Increased side-chain length of cationic residues led to reduced hydrophobicity till the side chains became more extended than the aromatic/hydrophobic side chains, at which point hydrophobicity increased slightly. Evaluation of antibacterial activity revealed that analogues with lowest hydrophobicity exhibited reduced activity against E. coli, while oligomers with the shortest cationic side chains were most potent against P. aeruginosa. Thus, membrane-disruptive interaction with P. aeruginosa appears to be promoted by a hydrophobic surface of the oligomers (comprised of the aromatic groups shielding the cationic side chains). Peptidomimetics with short cationic side chains exhibit increased hemolytic properties as well as give rise to decreased HepG2 (hepatoblastoma G2 cell line) cell viability. An optimal hydrophobicity window could be defined by a threshold of minimal hydrophobicity conferring activity toward E. coli and a threshold for maximal hydrophobicity, beyond which cell selectivity was lost.
Highlights
Increased emergence of bacterial strains resistant to antibiotics is a serious worldwide concern for human health
We explored how the hydrophobicity and activity profiles of a series of peptide/peptoid hybrid peptidomimetics depend on the structural features termed “relative side-chain length” and “nature of the more flexible residue”
A general trend within each subgroup was that increased cationic side-chain length confers gradually reduced hydrophobicity, since the amino functionalities become increasingly more accessible to the surroundings due to a lowered shielding by the aromatic groups of the hydrophobic residues. This effect was most distinct for analogues displaying the short cationic diaminobutyric acid (Dab) or NDab residues, as this feature conferred the highest hydrophobicity within each subgroup
Summary
Increased emergence of bacterial strains resistant to antibiotics is a serious worldwide concern for human health. Major factors contributing to the selection for multidrug-resistant (MDR) strains comprise the widespread non-prescription sales of antibiotics in some countries [1] and lack of rapid methods for identification of the specific bacteria causing an infection—with the ensuing prescription of inefficacious antibiotics [2]. Together, these issues promote development of resistance, which may give rise to pan-resistant strains due to inappropriate use of “last-resort”. It is not a viable long-term approach merely to develop analogues of existing drugs, since only entirely new classes of antibiotics may retain a prolonged usage time without the development of severe resistance problems.
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