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/anie.201809410

Cited by 23 publications

(27 citation statements)

References 26 publications

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“…[32][33][34][35][36][37][38] Thed esign of these antimicrobial agents is based on the attachment of membrane-anchoring hydrophobic residues to an aminoglycoside scaffold that is positively charged under physiological conditions.Antibiotics from the aminoglycoside class perturb the fidelity of bacterial translation by binding to the decoding A-site region of the bacterial ribosome;h owever, their target site is shifted from the ribosome to the plasma membrane through conjugation to one or more hydrophobic residues. [42] We observed that these antimicrobials rapidly accumulate in the cytosol causing the denaturation of macromolecules as well as organelle-membrane disruption (Figure 1B). [39][40][41] We recently synthesized inherently fluorescent antifungal cationic amphiphiles to study their effects on Candida yeast cells.…”

Section: Targeting the Plasma Membranementioning

confidence: 92%

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Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

2019

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The ratio between the dose of drug required for optimal efficacy and the dose that causes toxicity is referred to as the therapeutic window. This ratio can be increased by directing the drug to the diseased tissue or pathogenic cell. For drugs targeting fungi and malignant cells, the therapeutic window can be further improved by increasing the resolution of drug delivery to the specific organelle that harbors the drug's target. Organelle targeting is challenging and is, therefore, an under‐exploited strategy. Here we provide an overview of recent advances in control of the subcellular distribution of small molecules with the focus on chemical modifications. Highlighted are recent examples of active and passive organelle‐specific targeting by incorporation of organelle‐directing molecular determinants or by chemical modifications of the pharmacophore. The outstanding potential that lies in the development of organelle‐specific drugs is becoming increasingly apparent.

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Section: Targeting the Plasma Membranementioning

confidence: 92%

“…We recently synthesized inherently fluorescent antifungal cationic amphiphiles to study their effects on Candida yeast cells . We observed that these antimicrobials rapidly accumulate in the cytosol causing the denaturation of macromolecules as well as organelle‐membrane disruption (Figure B).…”

Section: Selective Targeting Of Subcellular Compartmentsmentioning

confidence: 99%

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

2019

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“…AKs are known to show their antimicrobial activity by increasing the membrane permeability of microorganisms [17,18,19,20,21]. Fluorogenic dyes, such as SYTOX TM green and propidium iodide (PI), are commonly employed for the study of membrane permeabilization (Figure 2).…”

Section: Introductionmentioning

confidence: 99%

Antifungal Activities of 4″,6″-Disubstituted Amphiphilic Kanamycins

et al. 2019

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Amphiphilic kanamycins derived from the classic antibiotic kanamycin have attracted interest due to their novel bioactivities beyond inhibition of bacteria. In this study, the recently described 4″,6″-diaryl amphiphilic kanamycins reported as inhibitors of connexin were examined for their antifungal activities. Nearly all 4″,6″-diaryl amphiphilic kanamycins tested had antifungal activities comparable to those of 4″,6″-dialkyl amphiphilic kanamycins, reported previously against several fungal strains. The minimal growth inhibitory concentrations (MICs) correlated with the degree of amphiphilicity (cLogD) of the di-substituted amphiphilic kanamycins. Using the fluorogenic dyes, SYTOXTM Green and propidium iodide, the most active compounds at the corresponding MICs or at 2×MICs caused biphasic dye fluorescence increases over time with intact cells. Further lowering the concentrations to half MICs caused first-order dye fluorescence increases. Interestingly, 4×MIC or 8×MIC levels resulted in fluorescence suppression that did not correlate with the MIC and plasma membrane permeabilization. The results show that 4″,6″-diaryl amphiphilic kanamycins are antifungal and that amphiphilicity parameter cLogD is useful for the design of the most membrane-active versions. A cautionary limitation of fluorescence suppression was revealed when using fluorogenic dyes to measure cell-permeation mechanisms with these antifungals at high concentrations. Finally, 4″,6″-diaryl amphiphilic kanamycins elevate the production of cellular reactive oxygen species as other reported amphiphilic kanamycins.

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“…It is well known that cationic amphiphiles are vectors for gene transfection [1,2] and antimicrobial agents [3,4]. Recently, great attention has been paid to the development of positively charged particles, as new targeted delivery systems with improved stability, selectivity, and other properties [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

“…Surface tension isotherms of surfactant solutions of Triton-X-100 (1, 2), SDS (3, 4), CTAB (5, 6), mono-CS-16(7,8), mono-CS-12 (9, 10), di-CS-16(11,12) in the absence(1,3,5,7,9,11) and presence(2,4,6,8,10,12) of furazolidone, 25°С.…”

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Nontoxic antimicrobial micellar systems based on mono- and dicationic Dabco-surfactants and furazolidone: Structure-solubilization properties relationships

Pashirova

Burilova

Лукашенко

et al. 2019

Journal of Molecular Liquids

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Self-assembly and solubilization properties of amphiphilic mono-and bisquaternized derivatives of 1,4diazabicyclo[2.2.2]octane (mono-CS-n and di-CS-n, where CScationic surfactant, n = 12, 14, 16, 18) was investigated by nuclear magnetic resonance with magnetic field pulse gradient. The influence of Dabco-surfactant structure (head group and length of alkyl chains) on critical micelle concentration and aggregation number of micelles was studied. The CMC of mono-CS-n are lower than CMC of di-CS-n. The aggregation numbers of mono-CS-n micelles are higher than for di-CS-n micelles. The solubilization capacity of mono-CS-n is higher than di-CS-n. The solubilization capacity of mono-CS-16 is 2.5 times higher than CTAB in the case of Orange OT as a solute, and it is close to CTAB in the case of Sudan I. The solubility of a poorly water-soluble antibacterial drug furazolidone was improved by micellar solubilization based on mono-and di-Dabco-surfactants. Mono-CSn is the best solubilizing agents toward furazolidone. The use of mixed composition mono-Dabco-16-furazolidone provides a significant increase in antimicrobial activity (by 2 times against bacteria and 8 times against fungi) and reduces by 2 times the dose of each of the components in combination formulation and causes b2% haemolysis of human red blood cells at the active dose.

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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 23 publications

References 26 publications

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

Guiding Drugs to Target‐Harboring Organelles: Stretching Drug‐Delivery to a Higher Level of Resolution

Antifungal Activities of 4″,6″-Disubstituted Amphiphilic Kanamycins

Nontoxic antimicrobial micellar systems based on mono- and dicationic Dabco-surfactants and furazolidone: Structure-solubilization properties relationships

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