Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

Jaber, Qais Z.; Benhamou, Raphael I.; Herzog, Ido M.; Baruch, Bar Ben; Fridman, Micha

doi:10.1002/ange.201809410

Cited by 8 publications

(5 citation statements)

References 27 publications

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“…First, 2j was incubated at 32 μg/mL, which is one, 1/4, and 1/2 of the MICs against F. graminearum, C. albicans MYA2876, and C. albicans 64124, respectively (Figure 3). Interestingly, fluorescence from 2j closely resembled previously reported images 30 and was observed to physically associate with cells of F. graminearum and the two C. albicans strains within 5 min of initial exposure. Therefore, it is likely that AKs not only caused fast membrane permeabilization but also quickly interacted with cells at concentrations lower than the corresponding MICs.…”

Section: ■ Results and Discussionsupporting

confidence: 84%

“…A recent report showed that AKs incorporated with fluorophores "rapidly accumulated in the cytosol and led to structural changes in proteins and DNA". 30 In the current study, we chose to use hydrophobic fluorophores instead of an alkyl chain/fluorophore combina-tion so that the overall structures of 2i and 2j would more closely resemble the amphipathic structural features of the AKs.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation

et al. 2019

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Amphiphilic aminoglycosides have attracted interest due to their novel antifungal activities. A crucial but often neglected factor for drug development in academia is cost of production. Herein is reported a one-step, inexpensive synthesis of amphiphilic alkyl kanamycins constituted with only natural components. The synthetic methodology also enabled the preparation of a series fluorescent amphiphilic aryl kanamycins for direct structure–activity mode of action studies. The lead compounds showed prominent antifungal activities against a panel of fungi, including Fusarium graminearum, Cryptococcus neoformans, and several Candida sp., and also significant antibacterial activities. With fluorescence-based whole cell assays, the aryl amphiphilic kanamycins were observed to permeabilize fungal surface membranes at faster rates than bacterial surface membranes. Also, the antifungal action of the amphiphilic kanamycins was observed to occur in a biphasic mode with an initial fast phase correlated with rapid membrane permeabilization at subminimal inhibitory concentrations and a slower phase membrane permeabilization that elevates the reactive oxygen species production leading to cell death. Inactive hydrophobic amphiphilic kanamycins displayed no membrane permeabilization. The results offer cost-effective methods for producing amphiphilic kanamycins and reveal insights into how nonfungal specific amphiphilic kanamycins can be employed for fungal specific diagnostic and therapeutic applications.

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Section: ■ Results and Discussionsupporting

confidence: 84%

Section: ■ Results and Discussionmentioning

confidence: 99%

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation

et al. 2019

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“…Previous study has reported that cationic amphiphiles could induce organelle decomposition and denaturation of protein and DNA through a necrotic process [13] . Therefore, we continued to examine if PGOx 10 similarly influenced the integrality of representative fungal organelles, such as the nucleus and mitochondria.…”

Section: Resultsmentioning

confidence: 98%

Short Guanidinium‐Functionalized Poly(2‐oxazoline)s Displaying Potent Therapeutic Efficacy on Drug‐Resistant Fungal Infections

et al. 2022

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New antifungals are urgently needed to combat invasive fungal infections, due to limited types of available antifungal drugs and frequently encountered side effects, as well as the quick emergence of drug‐resistance. We previously developed amine‐pendent poly(2‐oxazoline)s (POXs) as synthetic mimics of host defense peptides (HDPs) to have antibacterial properties, but with poor antifungal activity. Hereby, we report the finding of short guanidinium‐pendent POXs, inspired by cell‐penetrating peptides, as synthetic mimics of HDPs to display potent antifungal activity, superior mammalian cells versus fungi selectivity, and strong therapeutic efficacy in treating local and systemic fungal infections. Moreover, the unique antifungal mechanism of fungal cell membrane penetration and organelle disruption explains the insusceptibility of POXs to antifungal resistance. The easy synthesis and structural diversity of POXs imply their potential as a class of promising antifungal agents.

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“… 47 To ask if the antifungal activity of COL also is dependent upon its peptide charge, we tested three additional membrane-disrupting antimicrobials with different net charges for their ability to synergize with FLC ( Figure S9 ). Similar to COL (charge +5 47 ), RB163, a cationic amphiphile-derived from the aminoglycoside antibiotic tobramycin 48 (compound 3 in ref ( 48 )) synergized with FLC (FICI = 0.28 with 0.125 μg/mL FLC and 4 μg/mL RB163). By contrast, daptomycin (charge −3) 49 ( Figure S9C ) did not augment the activity of FLC.…”

Section: Resultsmentioning

confidence: 99%

“…Drug-exposed cultures were diluted 1:100 for 2–3 h in casitone followed by drug addition. Drugs were diluted in water (posaconazole (Sigma-Aldrich SML2287, >98%), colistin (Glentham Life Sciences GA9867, ≥19 000 U/mg), amphotericin B (TOKU-E, ≥95%), 5-fluorocytosine (Sigma-Aldrich F7129, ≥99%); ethanol (terbinafine T8826, ≥98%), fluconazole (Sigma-Aldrich F8929, ≥98%, ketoconazole (Sigma-Aldrich K1003, ≥99%), miconazole (Fischer Bioreagents, 98%), clotrimazole (Glentham Life Sciences, GA8137), caspofungin diacetate (Sigma-Aldrich SML0425, ≥19 000 IU/mg), anidulafungin (Sigma-Aldrich SML2288, ≥97%) myriocin (Sigma-Aldrich M1175, ≥98%), amphotericin B (A2411, ∼80%), daptomycin (Sigma-Aldrich D2446, ≥90%), RB163 48 (≥95%)) or DMSO (natamycin, Sigma-Aldrich, ≥95%). Casitone solid media (casitone liquid plus 10 g/L agar (Formedium, Ltd.)) was used for the disk assay method.…”

Section: Methodsmentioning

confidence: 99%

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

et al. 2021

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The increasing emergence of drug-resistant fungal pathogens, together with the limited number of available antifungal drugs, presents serious clinical challenges to treating systemic, life-threatening infections. Repurposing existing drugs to augment the antifungal activity of well-tolerated antifungals is a promising antifungal strategy with the potential to be implemented rapidly. Here, we explored the mechanism by which colistin, a positively charged lipopeptide antibiotic, enhances the antifungal activity of fluconazole, the most widely used orally available antifungal. In a range of susceptible and drug-resistant isolates and species, colistin was primarily effective at reducing fluconazole tolerance, a property of subpopulations of cells that grow slowly in the presence of a drug and may promote the emergence of persistent infections and resistance. Clinically relevant concentrations of colistin synergized with fluconazole, reducing fluconazole minimum inhibitory concentration 4-fold. Combining fluconazole and colistin also increased survival in a C. albicans Galleria mellonella infection, especially for a highly fluconazole-tolerant isolate. Mechanistically, colistin increased permeability to fluorescent antifungal azole probes and to intracellular dyes, accompanied by an increase in cell death that was dependent upon pharmacological or genetic inhibition of the ergosterol biosynthesis pathway. The positive charge of colistin is critical to its antifungal, and antibacterial, activity: colistin directly binds to several eukaryotic membrane lipids ( i.e. , l -α-phosphatidylinositol, l -α-phosphatidyl- l -serine, and l -α-phosphatidylethanolamine) that are enriched in the membranes of ergosterol-depleted cells. These results support the idea that colistin binds to fungal membrane lipids and permeabilizes fungal cells in a manner that depends upon the degree of ergosterol depletion.

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Cationic Amphiphiles Induce Macromolecule Denaturation and Organelle Decomposition in Pathogenic Yeast

Abstract: Cationic amphiphiles are alarge and diverse class of antimicrobial agents.

Cited by 8 publications

References 27 publications

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation

Development of Fungal Selective Amphiphilic Kanamycin: Cost-Effective Synthesis and Use of Fluorescent Analogs for Mode of Action Investigation

Short Guanidinium‐Functionalized Poly(2‐oxazoline)s Displaying Potent Therapeutic Efficacy on Drug‐Resistant Fungal Infections

Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

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