A Chemically Modified Tetracycline (CMT-3) Is a New Antifungal Agent

Abstract

Several chemically modified tetracycline analogs (CMTs), which were chemically modified to eliminate their antibacterial efficacy, were unexpectedly found to have antifungal properties. Of 10 CMTs screened in vitro, all exhibited antifungal activities, although their efficacies varied. Among these compounds, CMT-315, -3, and -308 were found to be the most potent as antifungal agents. The MICs of CMT-3 against 47 strains of fungi in vitro were determined by using amphotericin B (AMB) and doxycycline as positive and negative controls, respectively. The MICs of CMT-3 were generally found to be between 0.25 and 8.00 g/ml, a range that approximates the blood levels of this drug when administrated orally to humans. Of all the yeast species tested to date, Candida albicans showed the greatest sensitivity to CMT-3. The filamentous species most susceptible to CMT-3 were found to be Epidermophyton floccosum, Microsporum gypseum, Pseudallescheria boydii, a Penicillium sp., Scedosporium apiospermum, a Tricothecium sp., and Trichophyton rubrum. Growth inhibition of C. albicans by CMT-3, determined by a turbidity assay, indicated a 50% inhibitory concentration of 1 g/ml. Thirty-nine strains, including 20 yeasts and 19 molds, were used to measure viability (the ability to grow after treatment with a drug) inhibition by CMT-3 and AMB. CMT-3 exhibited fungicidal activity against most of these fungi, especially the filamentous fungi. Eighty-four percent (16 of 19) of the filamentous fungi tested showed more than 90% inhibition of viability by CMT-3. In contrast, AMB showed fungicidal activity against all yeasts tested. However, most of the filamentous fungi (16 of 19) showed less than 50% inhibition of viability by AMB, indicating that AMB is fungistatic against most of these filamentous fungi. To begin to identify the sites in fungal cells affected by CMT-3, C. albicans and a Penicillium sp. were incubated with the compound at 35°C, and then the fluorescence of CMT-3 was observed by confocal laser scanning electron microscopy. CMT-3 appeared to have widespread intracellular distribution throughout C. albicans and the Penicillium sp. The mechanisms of the antifungal activity of CMT-3 are now being explored.

Doxycycline Hydrogels as a Potential Therapy for Ocular Vesicant Injury

“…15 Therefore, we tested 4 tetracyclines as therapies against vesicants. Three tetracycline derivatives with antibiotic activity and one deaminated tetracycline, DDMT, which does not possess antibiotic activity, but does retain antimetalloproteinase activity, 36,40 were employed. The same number of nanomoles of each drug was used in experiments because the goal of this pilot project was to identify the best drug in the group quickly and inexpensively.…”

Étude du pouvoir antifongique de l’huile essentielle de cannelle

“…La gravit~ des candidoses [21,23], coupl~e fl l'insuffisance en m~dicaments efficaces, nous a conduit fl nous int6resser Penicilium cyclopium IP1231-8o ff10oo0 fi l'in~puisable source de produits naturels fi vertu th~rapeutique : les plantes m~dicinales [13,15,16,19,24,25]. A cot~ des m~dicaments synth~tiques prescrits dans le traitement des candidoses, beaucoup de produits naturels de par le monde ont ~t~ test~s dans le dessein de trouver un antifongique efficace, sans effets n~fastes et moins coflteux [13,15,16,19,24,25].…”

Structural responses of Daucus carota root-organ cultures and the arbuscular mycorrhizal fungus, Glomus intraradices, to 12 pharmaceuticals

“…The significant reduction in hyphal growth at 100 lg l À1 doxycycline is surprising as this compound is not considered to be an antifungal agent. In fact, doxycycline has been found to promote the overgrowth of fungi due to the suppression of normal microbiota (Liu et al, 2002). Tetracyclines have been reported to inhibit protein synthesis in mitochondria due to binding of the 70S ribosome (Chopra and Roberts, 2001) and the semi-synthetic, doxycycline, has been reported to have a wider spectrum of biological activity (Cunha, 1997).…”

“…The tetracycline family of compounds are selectively anti-bacterial and have few effects on eukaryotes (Chopra and Roberts, 2001) because of selective binding to the 30S subunit of bacterial ribosomes, resulting in the inhibition of protein synthesis (Liu et al, 2002). At high concentrations it has been suggested tetracycline toxicity on plants is induced directly through the chelating of metal nutrients (Nickell and Gordon, 1961;Brain et al, 2008).…”