Double-Headed Cationic Lipopeptides: An Emerging Class of Antimicrobials

Małuch, Izabela; Stachurski, Oktawian; Kosikowska-Adamus, Paulina; Makowska, Marta; Bauer, Marta; Wyrzykowski, Dariusz; Hać, Aleksandra; Kamysz, Wojciech; Deptuła, Milena; Pikuła, Michał; Sikorska, Emilia

doi:10.3390/ijms21238944

Cited by 10 publications

(6 citation statements)

References 48 publications

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“…Antimicrobial peptides (AMPs), also known as host defense peptides (HDPs), are a structurally and functionally diverse class of naturally occurring polypeptides that are evolutionarily conserved across all life forms [10][11][12][13][14][15]. AMPs form an integral component of the innate immune system in higher organisms.…”

Section: Introductionmentioning

confidence: 99%

Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action

Dash

Bhattacharjya

2021

IJMS

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Antimicrobial peptides (AMPs) possess great potential for combating drug-resistant bacteria. Thanatin is a pathogen-inducible single-disulfide-bond-containing β-hairpin AMP which was first isolated from the insect Podisus maculiventris. The 21-residue-long thanatin displays broad-spectrum activity against both Gram-negative and Gram-positive bacteria as well as against various species of fungi. Remarkably, thanatin was found to be highly potent in inhibiting the growth of bacteria and fungi at considerably low concentrations. Although thanatin was isolated around 25 years ago, only recently has there been a pronounced interest in understanding its mode of action and activity against drug-resistant bacteria. In this review, multiple modes of action of thanatin in killing bacteria and in vivo activity, therapeutic potential are discussed. This promising AMP requires further research for the development of novel molecules for the treatment of infections caused by drug resistant pathogens.

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Section: Introductionmentioning

confidence: 99%

Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action

Dash

Bhattacharjya

2021

IJMS

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“…In turn, the exothermic effects following subsequent titration steps may be attributed to the peptide–membrane electrostatic attraction and peptide folding. On the other hand, the peptide–membrane association can occur in parallel with other processes, such as a change in the lipid phase properties, increase in permeability of the membrane, micellization of the lipid bilayer or initial peptide aggregation [ 42 ]. Despite the biphasic isotherms, better fitting results were achieved using the “one set of site” binding model, which showed that the overall process was dominated by an unfavorable enthalpy change (Δ H > 0) offset by a large, favorable entropy change (TΔ S > 0).…”

Section: Resultsmentioning

confidence: 99%

“…All the peptides were synthesized on a Tenta Gel S RAM resin (0.22 mmol/g) according to previously described methodology [ 42 ]. After deprotection of the N-terminal part of the peptide chain with 20% piperidine in N,N-dimethylformamide (DMF), the modifications were performed using fatty acids with various carbon chain lengths (C 8 –C 16 ), (1-cyano-2-ethoxy-2-oxoethylidenaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) and N,N-diisopropylethylamine (DIPEA) of molar ratio peptide:fatty acid:COMU 1:3:3 (pH 8–9).…”

Section: Methodsmentioning

confidence: 99%

Lipidation of Naturally Occurring α-Helical Antimicrobial Peptides as a Promising Strategy for Drug Design

Makowska

Kosikowska-Adamus

Zdrowowicz

et al. 2023

IJMS

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In this paper, we describe the chemical synthesis, preliminary evaluation of antimicrobial properties and mechanisms of action of a novel group of lipidated derivatives of three naturally occurring α-helical antimicrobial peptides, LL-I (VNWKKVLGKIIKVAK-NH2), LK6 (IKKILSKILLKKL-NH2), ATRA-1 (KRFKKFFKKLK-NH2). The obtained results showed that biological properties of the final compounds were defined both by the length of the fatty acid and by the structural and physico-chemical properties of the initial peptide. We consider C8–C12 length of the hydrocarbon chain as the optimal for antimicrobial activity improvement. However, the most active analogues exerted relatively high cytotoxicity toward keratinocytes, with the exception of the ATRA-1 derivatives, which had a higher selectivity for microbial cells. The ATRA-1 derivatives had relatively low cytotoxicity against healthy human keratinocytes but high cytotoxicity against human breast cancer cells. Taking into account that ATRA-1 analogues carry the highest positive net charge, it can be assumed that this feature contributes to cell selectivity. As expected, the studied lipopeptides showed a strong tendency to self-assembly into fibrils and/or elongated and spherical micelles, with the least cytotoxic ATRA-1 derivatives forming apparently smaller assemblies. The results of the study also confirmed that the bacterial cell membrane is the target for the studied compounds.

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“…Then, bacteria were stained with a LIVE/DEAD™ BacLight™ Bacterial Viability Kit (ThermoFisher Scientific, Waltham, MA, USA) containing two dyes: a bacterial membrane-permeable Syto9 (green fluorescence) and a bacterial membrane-impermeable propidium iodide (red fluorescence), which stains only bacteria with damaged membranes. The details of the experiments were described previously [ 70 ].…”

Section: Methodsmentioning

confidence: 99%

Understanding the Role of Self-Assembly and Interaction with Biological Membranes of Short Cationic Lipopeptides in the Effective Design of New Antibiotics

et al. 2022

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This study investigates short cationic antimicrobial lipopeptides composed of 2–4 amino acid residues and C12-C18 fatty acids attached to the N-terminal part of the peptides. The findings were discussed in the context of the relationship among biological activity, self-assembly, stability, and membrane interactions. All the lipopeptides showed the ability to self-assemble in PBS solution. In most cases, the critical aggregation concentration (CAC) much surpassed the minimal inhibitory concentration (MIC) values, suggesting that monomers are the main active form of lipopeptides. The introduction of β-alanine into the peptide sequence resulted in a compound with a high propensity to fibrillate, which increased the peptide stability and activity against S. epidermidis and C. albicans and reduced the cytotoxicity against human keratinocytes. The results of our study indicated that the target of action of lipopeptides is the bacterial membrane. Interestingly, the type of peptide counterion may affect the degree of penetration of the lipid bilayer. In addition, the binding of the lipopeptide to the membrane of Gram-negative bacteria may lead to the release of calcium ions necessary for stabilization of the lipopolysaccharide layer.

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Double-Headed Cationic Lipopeptides: An Emerging Class of Antimicrobials

Cited by 10 publications

References 48 publications

Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action

Thanatin: An Emerging Host Defense Antimicrobial Peptide with Multiple Modes of Action

Lipidation of Naturally Occurring α-Helical Antimicrobial Peptides as a Promising Strategy for Drug Design

Understanding the Role of Self-Assembly and Interaction with Biological Membranes of Short Cationic Lipopeptides in the Effective Design of New Antibiotics

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