Antibacterial Properties and Mode of Action of a Short Acyl-Lysyl Oligomer

A promising class of potential new antibiotics are the antimicrobial peptides or their synthetic mimics. Herein we assess the effect of the type of cationic side chain (i.e., guanidino vs. amino groups) on the membrane perturbing mechanism of antimicrobial α-peptide–β-peptoid chimeras. Two separate Langmuir monolayers composed of 1,2-dipalmitoyl-sn-glycero-3-phosphatidylglycerol (DPPG) and lipopolysaccharide Kdo2-lipid A were applied to model the outer membranes of Gram-positive and Gram-negative bacteria, respectively. We report the results of the measurements using an array of techniques, including high-resolution synchrotron surface X-ray scattering, epifluorescence microscopy, and in vitro antimicrobial activity to study the molecular mechanisms of peptidomimetic interaction with bacterial membranes. We found guanidino group-containing chimeras to exhibit greater disruptive activity on DPPG monolayers than the amino group-containing analogues. However, this effect was not observed for lipopolysaccharide monolayers where the difference was negligible. Furthermore, the addition of the nitrobenzoxadiazole fluorophore did not reduce the insertion activity of these antimicrobials into both model membrane systems examined, which may be useful for future cellular localization studies.

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“…HRMS: m / z [M+3H] 3+ calcd for C 104 H 158 N 19 O 13 3+ : 627.07567, found: 627.07553 (ΔM: 0.22 ppm). [49]…”

Section: Methodsmentioning

confidence: 99%

“…This approach has been successfully used in conjunction with liquid surface X-ray scattering to study bacterial membrane lysis by human antimicrobial peptide LL-37,[60] protegrin-1[57, 62] gramicidin[63] and SMAP-29[61] antimicrobial peptides as well as by peptide mimics. [44, 59, 64, 65]…”

Section: Introductionmentioning

confidence: 99%

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

Andreev

Bianchi

Laursen

et al. 2014

Biochimica et Biophysica Acta (BBA) - Biomembranes

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“…Only very few studies have dealt with this problem, and in most published work, the possible AMP-induced mutation frequencies have been compared to the much higher mutation frequencies usually observed for conventional antibiotics. In general, previous studies have involved short-time evolution experiments [30], [31]. A single comprehensive study, focusing on continuous selection towards a magainin 2 analogue (pexiganan), showed that prolonged exposure to an AMP indeed may result in heritable resistance [29] despite the consensus that resistance against AMPs is unlikely to evolve.…”

Section: Introductionmentioning

confidence: 99%

Adaptive Evolution of Escherichia coli to an α-Peptide/β-Peptoid Peptidomimetic Induces Stable Resistance

et al. 2013

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Antimicrobial peptides (AMPs) and synthetic analogues thereof target conserved structures of bacterial cell envelopes and hence, development of resistance has been considered an unlikely event. However, recently bacterial resistance to AMPs has been observed, and the aim of the present study was to determine whether bacterial resistance may also evolve against synthetic AMP analogues, e.g. α-peptide/β-peptoid peptidomimetics. E. coli ATCC 25922 was exposed to increasing concentrations of a peptidomimetic (10 lineages), polymyxin B (10 lineages), or MilliQ water (4 lineages) in a re-inoculation culturing setup covering approx. 500 generations. All 10 lineages exposed to the peptidomimetic adapted to 32×MIC while this occurred for 8 out of 10 of the polymyxin B-exposed lineages. All lineages exposed to 32×MIC of either the peptidomimetic or polymyxin B had a significantly increased MIC (16–32×) to the selection agent. Five transfers (∼35 generations) in unsupplemented media did not abolish resistance indicating that resistance was heritable. Single isolates from peptidomimetic-exposed lineage populations displayed MICs against the peptidomimetic from wild-type MIC to 32×MIC revealing heterogeneous populations. Resistant isolates showed no cross-resistance against a panel of membrane-active AMPs. These isolates were highly susceptible to blood plasma antibacterial activity and were killed when plasma concentrations exceeded ∼30%. Notably, MIC of the peptidomimetic against resistant isolates returned to wild-type level upon addition of 25% plasma. Whole-genome sequencing of twenty isolates from four resistant lineages revealed mutations, in murein transglycosylase D (mltD) and outer-membrane proteins, which were conserved within and between lineages. However, no common resistance-conferring mutation was identified. We hypothesise that alterations in cell envelope structure result in peptidomimetic resistance, and that this may occur via several distinct mechanisms. Interestingly, this type of resistance result in a concomitant high susceptibility towards plasma, and therefore the present study does not infer additional concern for peptidomimetics as future therapeutics.

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“…For instance, the antibacterial OAK sequences C 12 K-7␣ 8 (39) and C 12 K-3␤ 10 (25) abruptly disrupted the plasma membrane, leading to quasi-immediate membrane depolarization/permeabilization, and death was typically observed within minutes. In contrast, C 12(7) K-␤ 12 (44) and NC 12-2␤ 12 (53) were clearly devoid of membranedisruptive properties despite their high binding affinity for reasonably suitable model membranes. They rather adhered to phospholipids in a shallow manner, thereby altering some of the fundamental membrane properties (e.g., charge density and fluidity).…”

Section: Discussionmentioning

confidence: 90%

“…Various lines of evidence suggest that the OAK approach is likely to help the development of useful antiinfective agents and could also generate valuable scientific information along the way: OAKs were shown to exert antibacterial activity in vitro and in vivo, regardless of secondary structure considerations (25,39,44). Their flexible chain arrangements can be made to vary in a myriad of alternatives (25,38), which have so far generated specific antitumor (15) and antiplasmodial (37) sequences, in addition to antibacterial sequences (39,42,53). They also provided insights into the complex mechanisms by which AMPs affect cell viability, having the ability to target either intracellular (15,42,43) or membranelinked (6,7,44) components.…”

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confidence: 99%

Antiplasmodial Properties of Acyl-Lysyl Oligomers in Culture and Animal Models of Malaria

Zaknoon

Wein

Krugliak

et al. 2011

Antimicrob Agents Chemother

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Our previous analysis of antiplasmodial properties exhibited by dodecanoyl-based oligo-acyl-lysyls (OAKs) has outlined basic attributes implicated in potent inhibition of parasite growth and underlined the critical role of excess hydrophobicity in hemotoxicity. To dissociate hemolysis from antiplasmodial effect, we screened >50 OAKs for in vitro growth inhibition of Plasmodium falciparum strains, thus revealing the minimal requirements for antiplasmodial potency in terms of sequence and composition, as confirmed by efficacy studies in vivo.

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Antibacterial Properties and Mode of Action of a Short Acyl-Lysyl Oligomer

Cited by 20 publications

References 60 publications

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

Guanidino groups greatly enhance the action of antimicrobial peptidomimetics against bacterial cytoplasmic membranes

Adaptive Evolution of Escherichia coli to an α-Peptide/β-Peptoid Peptidomimetic Induces Stable Resistance

Antiplasmodial Properties of Acyl-Lysyl Oligomers in Culture and Animal Models of Malaria

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