Peptaibol Analogs Show Potent Antibacterial Activity against Multidrug Resistant Opportunistic Pathogens

Torre, Chiara Dalla; Sannio, Filomena; Battistella, Mattia; Docquier, Jean Denis; Zotti, Marta De

doi:10.3390/ijms24097997

Cited by 3 publications

(1 citation statement)

References 57 publications

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“…Their sequences are characterized by the presence of many C α -tetrasubstituted Aib (α-aminoisobutyric acid; Figure 1) residues, a C-terminal 1,2-aminoalcohol and an N-terminal acyl group. They possess antimicrobial [16,17], antiviral [18] and antitumor [19,20] activity, even against drug-resistant cancer cell lines [21,22] and bacteria [23]. They are known to exert their bioactivity by interacting with the phospholipid membranes [24][25][26] through different mechanisms, depending mainly on the match between the thickness of the target membrane and the length of their helical 3D structure, which, in turn, depends on their sequence length.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Conformational Analysis and Antitumor Activity of the Naturally Occurring Antimicrobial Medium-Length Peptaibol Pentadecaibin and Spin-Labeled Analogs Thereof

Morbiato,

Quaggia,

Menilli

et al. 2023

IJMS

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Peptaibols are proteolysis-resistant, membrane-active peptides. Their remarkably stable helical 3D-structures are key for their bioactivity. They can insert themselves into the lipid bilayer as barrel staves, or lay on its surface like carpets, depending on both their length and the thickness of the lipid bilayer. Medium-length peptaibols are of particular interest for studying the peptide–membrane interaction because their length allows them to adopt either orientation as a function of the membrane thickness, which, in turn, might even result in an enhanced selectivity. Electron paramagnetic resonance (EPR) is the election technique used to this aim, but it requires the synthesis of spin-labeled medium-length peptaibols, which, in turn, is hampered by the poor reactivity of the Cα-tetrasubstituted residues featured in their sequences. After several years of trial and error, we are now able to give state-of-the-art advice for a successful synthesis of nitroxide-containing peptaibols, avoiding deleted sequences, side reactions and difficult purification steps. Herein, we describe our strategy and itsapplication to the synthesis of spin-labeled analogs of the recently discovered, natural, medium-length peptaibol pentadecaibin. We studied the antitumor activity of pentadecaibin and its analogs, finding potent cytotoxicity against human triple-negative breast cancer and ovarian cancer. Finally, our analysis of the peptide conformational preferences and membrane interaction proved that pentadecaibinspin-labeling does not alter the biological features of the native sequence and is suitable for further EPR studies. The nitroxide-containing pentadecaibins, and their synthetic strategy described herein, will help to shed light on the mechanism of the peptide–membrane interaction of medium-length peptaibols.

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Section: Introductionmentioning

confidence: 99%

Synthesis, Conformational Analysis and Antitumor Activity of the Naturally Occurring Antimicrobial Medium-Length Peptaibol Pentadecaibin and Spin-Labeled Analogs Thereof

Morbiato,

Quaggia,

Menilli

et al. 2023

IJMS

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Multiple lysine substitutions in the peptaibol trichogin GA IV enhance the antibiotic activity against plant pathogenic Pseudomonas syringae

Fodil,

De Zotti,

Tundo

et al. 2024

Pesticide Biochemistry and Physiology

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An Update on the Therapeutic Potential of Antimicrobial Peptides against Acinetobacter baumannii Infections

Rangel,

Lechuga,

Provance

et al. 2023

Pharmaceuticals

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The rise in antibiotic-resistant strains of clinically important pathogens is a major threat to global health. The World Health Organization (WHO) has recognized the urgent need to develop alternative treatments to address the growing list of priority pathogens. Antimicrobial peptides (AMPs) rank among the suggested options with proven activity and high potential to be developed into effective drugs. Many AMPs are naturally produced by living organisms protecting the host against pathogens as a part of their innate immunity. Mechanisms associated with AMP actions include cell membrane disruption, cell wall weakening, protein synthesis inhibition, and interference in nucleic acid dynamics, inducing apoptosis and necrosis. Acinetobacter baumannii is a critical pathogen, as severe clinical implications have developed from isolates resistant to current antibiotic treatments and conventional control procedures, such as UV light, disinfectants, and drying. Here, we review the natural AMPs representing primary candidates for new anti-A. baumannii drugs in post-antibiotic-era and present computational tools to develop the next generation of AMPs with greater microbicidal activity and reduced toxicity.

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Peptaibol Analogs Show Potent Antibacterial Activity against Multidrug Resistant Opportunistic Pathogens

Cited by 3 publications

References 57 publications

Synthesis, Conformational Analysis and Antitumor Activity of the Naturally Occurring Antimicrobial Medium-Length Peptaibol Pentadecaibin and Spin-Labeled Analogs Thereof

Synthesis, Conformational Analysis and Antitumor Activity of the Naturally Occurring Antimicrobial Medium-Length Peptaibol Pentadecaibin and Spin-Labeled Analogs Thereof

Multiple lysine substitutions in the peptaibol trichogin GA IV enhance the antibiotic activity against plant pathogenic Pseudomonas syringae

An Update on the Therapeutic Potential of Antimicrobial Peptides against Acinetobacter baumannii Infections

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