Multi-arm ε-polylysines exhibit broad-spectrum antifungal activities against <i>Candida</i> species

Cao, Yuanqiao; Liu, Ming; Han, Miaomiao; Ji, Shengxiang

doi:10.1039/d3bm01233f

Cited by 3 publications

(3 citation statements)

References 42 publications

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“…Six FAPs were synthesized by grafting tbutyloxy carbonyl (BOC)-protected linear L-lysine or Lornithine-based heptapeptoids onto a trimeric L-lysine core (4R), followed by removing protecting groups in trifluoroacetic acid (TFA). 30 The synthesis of a representative FAP, 4R-O7, is shown in Scheme 1a. Purification of these six FAPs was performed on an FPLC (GE healthcare) with a sephadex G25 column.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Four-Arm δ-Ornithine-Based Polypeptoids Resensitize Voriconazole against Azole-Resistant C. albicans

Cao,

Han,

2024

ACS Infect. Dis.

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Worldwide Candida albicans infections cause a huge burden in healthcare and the efficacy of traditional antifungals is diminished because of the rapid development of antifungal resistance. It is necessary to develop new antifungals or new strategies to make multidrug-resistant (MDR) C. albicans to resensitize to existing antifungal drugs. In this work, a series of 4arm polypeptoids (FAPs) were synthesized through grafting linear ε-L-lysine or δ-ornithine-based oligopeptides to a trimeric lysine core. The most potent 4R-O7 exhibited excellent activities toward three sensitive and two MDR C. albicans strains with MIC values as low as 24−48 μg/mL (vs 375 μg/mL for ε-polylysine, ε-PL). The mechanism studies revealed that 4R-O7 penetrated the cell membrane and generated ROS to kill cells. 4R-O7 exhibited a synergistic effect (FICI < 0.5) with voriconazole (VOR) and also assisted VOR to restore its efficacy to MDR C. albicans. In addition, the combined use of 4R-O7 and VOR significantly improved the elimination efficacy of mature C. albicans biofilms and enhanced the potency in a mouse subcutaneous C. albicans infection model.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Four-Arm δ-Ornithine-Based Polypeptoids Resensitize Voriconazole against Azole-Resistant C. albicans

Cao,

Han,

2024

ACS Infect. Dis.

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“…Several studies have suggested that the antifungal mechanism of AFPs may involve the participation of ROS . The generation of ROS has the potential to induce oxidative stress, resulting in detrimental effects such as cell membrane impairment and death in fungal cells .…”

Section: Resultsmentioning

confidence: 99%

“…Several studies have suggested that the antifungal mechanism of AFPs may involve the participation of ROS. 52 The generation of ROS has the potential to induce oxidative stress, resulting in detrimental effects such as cell membrane impairment and death in fungal cells. 53 To determine whether ROS mediates the killing mechanism of IR3 and VR3, we utilized 2,7-dichlorofluorescein diacetate (DCFH-DA) to detect intracellular ROS generation.…”

Section: Cell Wall Permeabilizationmentioning

confidence: 99%

Design of Proteolytic-Resistant Antifungal Peptides by Utilizing Minimum d-Amino Acid Ratios

Lai,

Yuan,

Chen

et al. 2024

J. Med. Chem.

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Antifungal peptides are an appealing alternative to standard antifungal medicines due to their unique mechanism of action and low-level resistance. However, their susceptibility to protease degradation keeps hindering their future development. Herein, a library was established to design peptides with protease resistance and high antifungal activity. The peptides were incorporated with minimal D-amino acids to further improve the protease stability. The most active peptide, IR3, demonstrated good antifungal activity and low toxicity, and its molecular integrity was maintained after protease hydrolysis for 8 h at 2 mg/mL. Furthermore, IR3 could permeate the fungal cell wall, disrupt the cell membrane, produce reactive oxygen species, and induce apoptosis in fungal cells. In vivo experiments confirmed that IR3 could effectively treat fungal keratitis. Collectively, these findings suggest that IR3 is a promising antifungal agent and may be beneficial in the design and development of protease-resistant antifungal peptides.

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Design and optimization of ε-poly-l-lysine with specific functions for diverse applications

Wang,

et al. 2024

International Journal of Biological Macromolecules

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Multi-arm ε-polylysines exhibit broad-spectrum antifungal activities against Candida species

Abstract: Multi-arm ε-polylysines (ε-mPLs, nR-Km) exhibit broad-spectrum antifungal activities and excellent biocompatibility. Mechanistic studies suggest that 3R-K7 kills fungi through entering the cells to generate ROS and induce cell apoptosis.

Cited by 3 publications

References 42 publications

Four-Arm δ-Ornithine-Based Polypeptoids Resensitize Voriconazole against Azole-Resistant C. albicans

Four-Arm δ-Ornithine-Based Polypeptoids Resensitize Voriconazole against Azole-Resistant C. albicans

Design of Proteolytic-Resistant Antifungal Peptides by Utilizing Minimum d-Amino Acid Ratios

Design and optimization of ε-poly-l-lysine with specific functions for diverse applications

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