Antifungal amphiphilic aminoglycosides

Chang, Cheng‐Wei Tom; Takemoto, Jon Y.

doi:10.1039/c4md00078a

Cited by 51 publications

(58 citation statements)

References 46 publications

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“…The MIC values of C 6 to C 14 determined in this study were mostly consistent with previously reported MIC values of these analogues against the specific strains of bacteria (7). Recently, the amphiphilic kanamycin A and B derivatives K20 and FG08, respectively, with C 8 linear alkyl chains were shown to have promising antifungal properties with no or mild antibacterial properties, respectively (8)(9)(10). This report has motivated us to explore the potential antifungal activities of our C 4 to C 14 TOB analogues that were yet to be determined.…”

Section: Discussionsupporting

confidence: 77%

“…Similarly, the IC 50 s of C 12 against both cell lines were Ն125 mg/liter, 4-to 64-fold higher than its antifungal MICs. However, C 4 , C 6 , C 8 , C 10 , and TOB itself show little to no toxicity against these cell lines.…”

Section: Resultsmentioning

confidence: 99%

“…However, the antifungal activities of these analogues are yet to be determined. It was recently reported that the incorporation of a C 8 linear alkyl chain at the O-4Љ-position and of an octanesulfonyl chain at the O-6=-position of kanamycins A and B, respectively, led to the discovery of new applications of these AGs as antifungal agents that lack bacterial activity (8)(9)(10)(11). This prompted us to investigate the antifungal properties of our 6Љ-thioether TOB analogues with linear alkyl chains with chain lengths between C 4 and C 14 (here, we are referring to these as C 4 , C 6 , C 8 , C 10 , C 12 , and C 14 ) ( Fig.…”

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confidence: 99%

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Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Shrestha

Fosso

Green

et al. 2015

Antimicrob Agents Chemother

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In this study, we investigated the in vitro antifungal activities, cytotoxicities, and membrane-disruptive actions of amphiphilic tobramycin (TOB) analogues. The antifungal activities were established by determination of MIC values and in time-kill studies. Cytotoxicity was evaluated in mammalian cell lines. The fungal membrane-disruptive action of these analogues was studied by using the membrane-impermeable dye propidium iodide. TOB analogues bearing a linear alkyl chain at their 6؆-position in a thioether linkage exhibited chain length-dependent antifungal activities. Analogues with C 12 and C 14 chains showed promising antifungal activities against tested fungal strains, with MIC values ranging from 1.95 to 62.5 mg/liter and 1.95 to 7.8 mg/liter, respectively. However, C 4 , C 6 , and C 8 TOB analogues and TOB itself exhibited little to no antifungal activity. Fifty percent inhibitory concentrations (IC 50 s) for the most potent TOB analogues (C 12 and C 14 ) against A549 and Beas 2B cells were 4-to 64-fold and 32-to 64-fold higher, respectively, than their antifungal MIC values against various fungi. Unlike conventional aminoglycoside antibiotics, TOB analogues with alkyl chain lengths of C 12 and C 14 appear to inhibit fungi by inducing apoptosis and disrupting the fungal membrane as a novel mechanism of action. Amphiphilic TOB analogues showed broad-spectrum antifungal activities with minimal mammalian cell cytotoxicity. This study provides novel lead compounds for the development of antifungal drugs.

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Section: Discussionsupporting

confidence: 77%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Shrestha

Fosso

Green

et al. 2015

Antimicrob Agents Chemother

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“…8,10,12,15,18 Aminoglycosides also show promise as treatments for other diseases, including HIV 2 ; human genetic disorders, where their ability to induce miscoding has been used to suppress disease-associated premature termination codons 2,19 ; and fungal infection, where amphiphilic aminoglycoside analogs have been shown to perturb the function of the fungal plasma membrane. 20 …”

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confidence: 99%

Detection and Quantification of Ribosome Inhibition by Aminoglycoside Antibiotics in Living Bacteria Using an Orthogonal Ribosome-Controlled Fluorescent Reporter

2015

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The ribosome is the quintessential antibacterial drug target, with many structurally and mechanistically distinct classes of antibacterial agents acting by inhibiting ribosome function. Detecting and quantifying ribosome inhibition by small molecules and investigating their binding modes and mechanisms of action are critical to antibacterial drug discovery and development efforts. To develop a ribosome inhibition assay that is operationally simple, yet provides direct infonnation on drug target and mechanism of action, we have developed engineered E. coli strains harboring an orthogonal ribosome-controlled green fluorescent protein (GFP) reporter that produce fluorescent signal when the orthogonal ribosome is inhibited. As a proof of concept, we demonstrate that these strains, when co-expressing homogenous populations of aminoglycoside resistant ribosomes, act as sensitive and quantitative detectors of ribosome inhibition by a set of twelve structurally diverse aminoglycoside antibiotics. We suggest that this strategy can be extended to quantifying ribosome inhibition by other drug classes.

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“…From in-vitro inhibition test of the antibiotic kanamycin of phage R17 RNA, it was found that kanamycin B has a stronger activity than kanamycin A, while kanamycin C has the weakest activity compared to both kanamycin A and B [28][29]. More researches have been devoted to chemical modification of aminoglycoside antibiotics such as kanamycin with the goal of increasing antibacterial activities or new activities as antibacterial [30][31][32][33]. Tc-kanamycin labeling studies have been carried out in the previous research by the indirect method using pyrophosphate as a co-ligand with the result of labeling efficiency of above 95% [34][35][36].…”

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confidence: 99%

Preparation of <sup>99m</sup>Tc-Kanamycin Using a Direct Labeling Method

et al. 2016

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Infectious diseases are still the leading cause of death in the world. The accurate technique for early detection and determination of the exact location of infection in the body is still needed. Nuclear techniques are capable for this purpose while other techniques such as MRI, USG and CT-SCAN sometimes cannot be applied. Tckanamycin radiopharmaceutical is complex of kanamycin and technetium-99m radionuclide, was used for bacterial detection of infection. The labeling studies of 99m Tc-kanamycin has been carried out by the indirect labeling method using pyrophosphate as a co-ligand with the results of labeling efficiency above 95%. However, the presence of radiochemical impurities in the form of 99m Tcpyrophosphate in the indirect labeling have to be considered which may interfere the imaging result. This study aimed to determine the optimum labeling conditions of Tc-kanamycin by direct labeling method. Kanamycin was successfully labeled with technetium-99m through direct labeling method. The labeling efficiency was determined by ascending paper chromatography using Whatman 3 paper as the stationary phase, and acetone as the mobile phase to separate the radiochemical impurities in the form of 99m Tc-pertechnetate. While impurities in the form of 99m Tcreduced were separated using the stationary phase ITLC-SG and 0.5 N NaOH as mobile phase. The experiment result showed that the optimum labeling conditions obtained by using 5 mg kanamycin, 30 µg SnCl 2 .2H 2 O, and pH of labeling was 9. The incubation time of labeling was 30 min at room temperature, provided labeling efficiency of 92.31 ± 1.74 %. The successful of kanamycin labeling with high efficiency makes 99m Tc-kanamycin can potentially be used as a radiopharmaceutical for the early detection of infectious diseases.

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Antifungal amphiphilic aminoglycosides

Cited by 51 publications

References 46 publications

Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Amphiphilic Tobramycin Analogues as Antibacterial and Antifungal Agents

Detection and Quantification of Ribosome Inhibition by Aminoglycoside Antibiotics in Living Bacteria Using an Orthogonal Ribosome-Controlled Fluorescent Reporter

Preparation of <sup>99m</sup>Tc-Kanamycin Using a Direct Labeling Method

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