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Eleven quinazolones were synthesized by condensing 2-phenylanthranil with a suitable peptide in pyridine. The compounds synthesized were characterised by their sharp melting points, elemental analysis and IR spectra. The newly synthesized compounds were tested for their amoebicidal and fungicidal activities. Some of the compounds showed promising results.
Human polymorphonuclear leukocytes (PMN) are a first line of defense against fungal infections. PMN express numerous pattern recognition receptors (PRR) that facilitate identification of invading microorganisms and ultimately promote resolution of disease. Dectin-1 (beta-glucan receptor) is a PRR expressed on several cell types and has been studied on monocytes and macrophages. However, the role played by dectin-1 in the recognition and killing of fungi by PMN is unknown. We investigated the ability of dectin-1 to mediate human PMN phagocytosis and fungicidal activity. Dectin-1 was expressed on the surface of PMN from all subjects tested (n=29) and in an intracellular compartment that co-sedimented with azurophilic granules in Percoll density gradients. Soluble beta-glucan and mAb GE2 (anti-dectin-1) inhibited binding and phagocytosis of zymosan by human PMN (e.g., ingestion was inhibited 40.1% by 30 min, p<0.001), and blocked reactive oxygen species production. Notably, soluble beta-glucan and GE2 inhibited phagocytosis and killing of Candida albicans by PMN (inhibition of killing was 54.8% for beta-glucan and 36.2% for GE2, p<0.01). Our results reveal a mechanism whereby PMN dectin-1 plays a key role in the recognition and killing of fungal pathogens by the innate immune system.
We investigated the photomutagenicity of thiabendazole (TBZ), a postharvest fungicide commonly used on imported citrus fruits. Using UVA light (320-400 nm), we irradiated bacterial cultures with or without TBZ in a 24-well multiplate. UVA-irradiation without TBZ was not mutagenic to the tester strains, nor was unirradiated TBZ. TBZ was strongly photomutagenic in Escherichia coli WP2uvrA and WP2uvrA/pKM101 strains, weakly photomutagenic in Salmonella typhimurium TA100 and TA98, and not photomutagenic in S. typhimurium TA1535 and TA1538. The photomutagenicity of TBZ was more evident in WP2uvrA/pKM101, which carries the trpE65 ochre mutation (TAA), than in TA100, which carries the hisG46 missense mutation (CCC). In E. coli WP3101-WP3106 and the corresponding pKM101-containing strains, photoactivated TBZ induced predominantly G:C-->A:T transitions and A:T-->T:A transversions. In the plasmid-containing strains only, TBZ induced a moderate number of A:T-->G:C transitions and a few A:T-->C:G and G:C-->T:A transversions. The observation that UVA-irradiated TBZ mutated both G:C and A:T basepairs may explain why WP2uvrA/pKM101 was more sensitive to its mutagenicity than TA100. TBZ that was irradiated before it was added to the WP2uvrA/pKM101 cells was not photomutagenic, which suggests that the photomutagenic products of TBZ were unstable or rapidly reacted with other molecules before being incorporated into cells.
A series of experiments show the potency of a newly described microbicidal system, involving iron, H2O2, and halide, in killing a fungus (Blastomyces dermatitidis). B dermatitidis has previously been shown susceptible to the myeloperoxidase-H2O2-halide system. The present studies show killing of either of two strains in 1 hour if Fe++ at 5 X 10(-5)M, H2O2 at 5 X 10(-5)M and Kl at 5 X 10(-4)M are all present (P less than 0.001). EDTA, a Fe++ chelator, abrogates killing. The mechanism presumably utilizes hydroxyl radical, since an inhibitor, ethanol, also neutralizes the system. The bactericidal and fungicidal system is of great potential importance in vivo.
BACKGROUND AND OBJECTIVE: Denture stomatitis (DS) is a common inflammatory condition that affects denture wearers. The aim of this study was to examine, in vivo, the effect of diode laser irradiation on fungal growth in both the palatal mucosa and in denture base materials, in denture wearing patients. STUDY DESIGN/MATERIALS AND METHODS: In total, 70 patients with clinical study design evidence of DS participated in this parallel, single blind, and placebo controlled study. The subjects were randomly assigned to one of four different treatment regimens: (1) irradiation with a 685 nm wavelength laser for 10 minutes (30 mW); (2) irradiation with a 830 nm wavelength laser for 5 minutes (60 mW). A semiconductor diode laser, BTL-2000 (BTL-2 Dravotnicka Technika, Prague, Czech Republic), was used in both treatment cases using an energy density of 3.0 J/cm(2) and a continuous working mode for five consecutive days; (3) placebo-sham irradiation of patients; (4) antimicotic-self treatment of patient's palatal mucosa with an antifungal oral gel and the use of an antiseptic solution for their dentures. The effect of laser light on fungal growth in vivo was evaluated after final treatment using the swab method and a semi-quantitative estimation of Candida albicans colonies cultivated on agar plates. RESULTS: A fungicidal effect was achieved in the laser treated and antimicotic treated groups, whereas most subjects in the placebo group were found to have unchanged conditions on both their palate (P = 0,004) and dentures (P < 0,001). CONCLUSIONS: Light from a low-power laser (LLLT) may be valuable in the treatment of DS. This is of great importance since the rate of recurrence of disease is high, whereas an optimal treatment modality has not yet been found.
Anethole shows synergistic effects on the antifungal activities of phytochemicals including polygodial and (2E)-undecenal against Saccharomyces cerevisiae and Candida albicans. It was found that a fungistatic dodecanol combined with a sublethal amount of anethole showed a fungicidal activity against S. cerevisiae. The MIC of dodecanol quickly reduced cell viability, but the cell viability recovered shortly after and then finally became no longer different from the control, indicating that the effect of dodecanol on this yeast was classified as sublethal damage. On the other hand, anethole completely restricted the recovery of cell viability. Therefore the expression of the synergistic effect was probably due to a blockade of the recovery process from dodecanol-induced stress.
The cytotoxic and mutagenic effects of the fungicides mancozeb and thiram were studied using human peripheral blood lymphocytes cultured in vitro with or without an S-9 mix microsomal metabolizing system. The results obtained suggested that the chemicals caused dose-dependent inhibition of thymidine uptake and unscheduled DNA synthesis on both resting and proliferating lymphocytes in the absence of the S-9 mix. In the presence of the S-9 mix, only thiram showed mutagenic activity by eliciting unscheduled DNA synthesis and a significantly higher frequency of sister chromatid exchanges than did controls.
The fungicides thiram and ziram have been assayed in a battery of nine bacterial strains of different genetic specificity. The results obtained suggest the induction of excisable DNA lesion(s), and indicate similar mutability of strains with AT or GC base pairs at target sites. This mutagenic profile is clearly distinct from that of oxidative mutagens, and it does not support the proposed role of oxidative stress in the mechanism of dithiocarbamates mutagenicity in bacteria. Furthermore, the bone marrow micronucleus test has been carried out in B6C3F1 mice with intraperitoneal administration of high grade thiram (12.5-50 mg/kg) and ziram samples (2.5-10 mg/kg in males, and 5-20 mg/kg in females). Thiram produced a significant increase of micronucleated PCEs in male mice sampled 48 h after treatment with 25, 37.5, and 50 mg/kg. No significant increase was detected in treated females. Ziram, tested in a lower range of doses because of its higher toxicity, resulted negative in both sexes. Both the acute toxicity and the ratio polychromatic/normochromatic erythrocytes indicated some sex specificity in the toxic effects induced by these dithiocarbamates in the B6C3F1 mouse.
We report here the results obtained using the dithiocarbamate fungicides thiram and ziram to investigate the induction of chromosomal aberrations (CAs) in Chinese hamster ovary (CHO) cells both in the absence and presence of S9 metabolism, and in a Chinese hamster epithelial liver (CHEL) cells which retain metabolic competence to activate different classes of promutagens/procarcinogens. Both thiram and ziram proved to be strong chromosome breaking agents in the CHEL cells and CHO cells in the presence of S9 metabolism. These findings suggest that thiram and ziram require metabolic conversion to become genetically active, and corroborate the evidence that CHEL cells are suitable to activate and detect a broad spectrum of chemical procarcinogens including these two pesticides.
The ecological relevance of the neutral red retention assay as a biomarker in an indigenous earthworm population (Microchaetus sp.) exposed to the fungicide copper oxychloride was investigated. Changes in earthworm biomass and numbers were monitored and related to changes in neutral red retention times of coelomocytes as well as changes in copper concentrations in the soil and earthworm body tissues. Results indicated that Microchaetus sp. responded sensitively to the copper oxychloride by showing an initial decrease in biomass 2 months after spraying started. This was followed by a significant decrease in worm numbers after 3 months. The neutral red retention times of earthworm coelomocytes decreased significantly within the first month of treatment and correspond to a significant increase in soil copper concentrations, but not with an immediate increase in body burdens of copper. More than a year after spraying had stopped the worm biomass and numbers were still significantly lower in the treated plots compared with the control plots. Since the reduction in neutral red retention times could be attributed to the presence of copper oxychloride and preceded the decline in population density and biomass, we conclude that this biomarker has a useful role to play in environmental risk assessment and could provide a warning of impending ecological damage.
An Ustilago maydis ergosterol biosynthesis mutant (A14) which is partially blocked in sterol 14alpha-demethylase (P45014DM) activity is described. This mutant accumulated the abnormal 14alpha-methyl sterols, eburicol, 14alpha-methylfecosterol, and obtusifoliol, along with significant amounts of ergosterol. Although the A14 mutant grew nearly as well as the wild type, it was impaired in cell extension growth, which indicated a dysfunction in apical cell wall synthesis. The mutant was also found to be hypersensitive to the azole fungicides penconazole and tebuconazole.
Survival of microorganisms in natural environments is favored by the capacity to produce compounds toxic to competing organisms and the ability to resist the effects of such toxic compounds. Both factors contribute to a competitive advantage of organisms in ecosystems. All organisms have evolved active transport mechanisms by which endogenous and exogenous toxicants can be secreted. Two major classes of transporter proteins are the ATP-binding cassette (ABC) and the major facilitator superfamily (MFS) transporters. Members of both classes can have broad and overlapping substrate specificities for natural toxic compounds and can be regarded as a "first-line defense barrier" in survival mechanisms. In plant pathogens, these transporters can play an essential role in protection against plant defense compounds during pathogenesis. Also, some transporters actively secrete host-specific and non-host-specific toxins. Remarkably, ABC and MFS transporters can also play a major role in fungicide sensitivity and resistance. Their role in multidrug resistance of Aspergillus nidulans, Candida albicans, and Saccharomyces cerevisiae to azoles and other fungitoxic compounds is well established. Knowledge of ABC and MFS transporters opens possibilities of developing novel strategies for controlling plant diseases, either by modulation of transporter activity or by transgenic expression of transporter genes in plants.
With implementation of the Food Quality Protection Act (FQPA), questions have been raised concerning the adequacy of current guideline testing under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) to assure compliance with FQPA. Specifically, there have been questions about whether FIFRA testing is adequate to assure protection of the most sensitive individuals in the population that might be exposed to FIFRA-regulated chemicals. In most cases, concern has been expressed about protection of infants and children. One way to examine the adequacy of current testing is to retrospectively examine data generated from tests similar to, or the same as, standard FIFRA tests on chemicals with known effects on developing organisms, effects that occur at doses below the effect level for adults. Lead is an example of a compound that has been widely studied and where infants and children have been shown to be more susceptible than adults to certain types of lead-induced toxicity. A review of the available animal toxicity studies on lead compounds, studies that were similar in design to testing required under FIFRA, was performed and the adequacy of the studies for setting human exposure levels that would be protective of child and infant health was assessed. The assessment demonstrated that current guideline testing under FIFRA would have resulted in setting of an exposure level in humans that is below the current regulatory action level for lead, without the use of an additional FQPA safety factor.
A gene which confers resistance to the systemic fungicide carboxin (Cbx) has been isolated from the maize pathogen, Ustilago maydis, by transferring a plasmid gene library from a Cbx-resistant mutant strain into a sensitive strain and selecting for expression of the resistance gene. Five plasmids, rescued from transformants which exhibited enhanced resistance to Cbx, were shown to have DNA inserts with common restriction enzyme fragments. All the plasmids transformed a sensitive U. maydis strain to Cbx resistance. The gene (Cbxr), sub-cloned on a 3.2 kb EcoR1-HindIII fragment, transformed U. maydis to Cbx resistance at frequencies similar to those obtained with the bacterial Hygromycin B resistance (HygBr) gene. The sequence of the Cbxr gene showed a high degree of homology to succinate dehydrogenase (EC 1.3.99.1) iron-sulphur subunit genes from other organisms.
Capillary gas chromatographic (GC) methods using sulphur and mass selective detection for the qualitative and quantitative determination of tetrahydrophtalimide (THPI) and 2-thiothiazolidine-4-carboxylic acid (TTCA), urinary metabolites of the fungicide captan in rat and humans, were developed. Urinary detection limits were 2.7 micrograms/l for THPI and 110 micrograms/l for TTCA. Intraperitoneal and oral administration of captan to rats resulted in a 48-h cumulative urinary excretion of THPI of 1%-2% and 3%-9% of the dose, respectively. Cumulative urinary excretion of TTCA over 48 h ranged from 2% to 5% of the captan dose for the respective routes of administration. In urine of non-exposed human subjects, neither THPI nor TTCA could be detected. In urine of fruit-growers who were occupationally exposed to captan, both THPI and TTCA could be detected. Based on these results, THPI and TTCA are proposed as promising parameters for the biological monitoring of occupational exposure to captan.
The use of a plant fungicide, the imidazole imazalil, in the therapy of human alternariosis is described. The patient's disease involved the palate, nose and sinuses, and had been unresponsive to conventional therapy. Imazalil has been used to treat Alternaria infections of plant materials. The patient's isolate was susceptible in vitro. We also showed that the drug was inhibitory to fungi in vitro as a vapor, not requiring contact by diffusion through agar or broth. The drug was used topically, by installation and irrigation, in this case and administered orally in doses of up to 1 200 mg daily, for 6 months. Peak serum concentrations exceeded 4 mcg/ml. The infection was arrested but not cured. The drug was tolerated without evident toxicity, though an unpleasant taste and nausea at high doses were limiting.
House-dust mites (Pyroglyphidae) are an important source of indoor airborne allergens. Several methods may be applied to reduce the population growth of these mites and thus the quantity of allergen formed. One such method is to interfere with the mites' food chain. Fungi are a key factor in this food chain: they serve as an indirect food source. In this study we investigated the results of the repeated application of a fungicide (natamycin) on mattresses. As controls we treated some mattresses with a placebo, while others were left untreated. The application of natamycin appeared to hamper mite development. Additional vacuuming reduced the quantity of mite allergens present. In the usual household situation repeated treatment will be necessary to obtain a long-term reduction.
The efficacy of a fungicidal preparation, natamycin, for the effective control of Dermatophagoides pteronyssinus (Trouessart), was determined at different concentrations on mattress-dust microsites, including ticking. One treatment with the commercially available natamycin concentration (Tymasil) resulted in a 65% reduction of house-dust mite populations within 4 weeks of treatment. The acaricidal control could be proven despite the protective role of mattress fibres such as ticking. However, mite fecundity was much more affected after treatment with twice the commercial concentration, which then assured a long-term control. Concentrations below the commercially available one were not effective. In a maritime climate, six sequential treatments three times a year would be effective for an adequate long-term control because of the high growth of house-dust fungi and the close interaction between the mite and the mould Aspergillus penicilloides.