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PubMed1999

LY303366 exhibits rapid and potent fungicidal activity in flow cytometric assays of yeast viability.

LY303366 is a semisynthetic analog of the antifungal lipopeptide echinocandin B that inhibits (1,3)-beta-D-glucan synthase and exhibits efficacy in animal models of human fungal infections. In this study, we utilized flow cytometric analysis of propidium iodide uptake, single-cell sorting, and standard microbiological plating methods to study the antifungal effect of LY303366 on Saccharomyces cerevisiae and Candida albicans. Our data indicate that an initial 5-min pulse treatment with LY303366 caused yeasts to take up propidium iodide and lose their ability to grow. Amphotericin B and cilofungin required longer exposure periods (30 and 180 min, respectively) and higher concentrations to elicit these fungicidal effects. These two measurements of fungicidal activity by LY303366 were highly correlated (r > 0.99) in concentration response and time course experiments. As further validation, LY303366-treated yeasts that stained with propidium iodide were unable to grow in single-cell-sorted cultures. Our data indicate that LY303366 is potent and rapidly fungicidal for actively growing yeasts. The potency and rapid action of this new fungicidal compound suggest that LY303366 may be useful for antifungal therapy.

Anidulafungin↗
PubMed2005

Comparison of the fungicidal activities of caspofungin and amphotericin B against Candida glabrata.

We investigated the fungicidal activity of caspofungin (CAS) and amphotericin B (AMB) against 16 clinical isolates of Candida glabrata. The minimum fungicidal concentrations (MFCs) of CAS were similar to those of AMB, ranging from 2.0 to >8.0 microg/ml. Time-kill assays performed on selected isolates showed that AMB was fungicidal at concentrations four times the MIC while CAS was not. A neutropenic-mouse model of disseminated infection was utilized to determine the residual fungal kidney burden. While doses as low as 0.3 and 1 mg/kg of body weight/day of CAS and AMB, respectively, were effective at reducing the counts with respect to controls, organ sterilization was reached when both drugs were administered at 5 mg/kg/day. Our study reveals that, similar to AMB, CAS has the potential for a fungicidal effect in vivo against this difficult-to-treat fungal pathogen.

Amphotericin B↗
PubMed2004

Determination of fungicidal activities against yeasts and molds: lessons learned from bactericidal testing and the need for standardization.

In certain unique clinical settings, the ability of the antimicrobial agent administered to kill the pathogen outright may be quite important. These situations invariably involve infection of a site not easily accessed by host defenses and/or of a structure with essential anatomic or physiologic function such as the heart (endocarditis), central nervous system (meningitis), or bone (osteomyelitis). Likewise, infections in immunosuppressed hosts, especially those who are neutropenic, are often thought to require microbicidal therapy. Proof of the cidal nature of an antimicrobial agent in vitro is tedious, complex, and fraught with error. Although several methods for assessing in vitro bactericidal activity have been standardized (NCCLS M26-A and M21-A), the clinical relevance of these determinations is questionable and the tests are performed infrequently in most laboratories. Most of the clinical data supporting the need for microbicidal therapy and testing have focused on bacterial infections. However, given the fact that most serious fungal infections occur in profoundly immunosuppressed individuals, it is generally assumed that a cidal regimen would be preferable in that setting as well. In view of this clinical concern and the perceived need to assess the fungicidal activity of a variety of agents, we considered that it would be useful to review what is known about the issues and problems in assessing bactericidal activity and the clinical utility of such measurements. Following this review, we discuss the issue of how one defines fungicidal activity in vitro and in vivo and how feasible it might be to determine the fungicidal activity of organism-drug combinations for purposes of both drug development and clinical care. Proposed methods for fungal time-kill determinations and minimal fungicidal concentration determinations are also discussed.

Animals↗
PubMed1989

Tumor necrosis factor alpha potentiates neutrophil antimicrobial activity: increased fungicidal activity against Torulopsis glabrata and Candida albicans and associated increases in oxygen radical production and lysosomal enzyme release.

The capacity of human tumor necrosis factor alpha (TNF-alpha) to modulate the killing of the opportunistic pathogens Torulopsis glabrata and Candida albicans by human neutrophils was studied. TNF-alpha significantly enhanced neutrophil fungicidal activity in a concentration-dependent manner and was evident in a range of neutrophil-fungus ratios. Enhanced killing of T. glabrata required much lower TNF-alpha concentrations than were required for enhancement of killing of C. albicans. Maximal enhancement of killing occurred with 20 and 100 U of TNF-alpha per 5 x 10(6) neutrophils for T. glabrata and C. albicans, respectively. The fungal killing kinetics demonstrated that TNF-alpha augmentation of fungicidal activity was evident within 1 h and persisted for an incubation period of at least 22 h. Preincubation of neutrophils with TNF-alpha was essential for the enhancement of killing. Maximal stimulation of killing was observed within 1 h of preincubation with TNF-alpha, and poor stimulation of killing was observed when TNF-alpha was added at time zero. Associated with the increase in fungicidal activity was an increased production of superoxide and an enhanced degranulation of enzymes and other proteins from azurophilic and specific granules in response to the fungi. The results demonstrate that TNF-alpha augments the neutrophil oxidative respiratory burst and the degranulation induced by opsonized fungi and that it increases the neutrophil fungicidal activity.

Adjuvants, Immunologic↗
PubMed1997

Rationale and perspectives on the development of fungicides.

Fungicides continue to be essential for the effective control of plant diseases. New classes of fungicides with novel modes of action are being developed in the 1990s. These include the strobilurins, phenylpyrroles, anilinopyrimidines, phenoxyquinolines, and compounds that trigger defense mechanisms in the plant. For the foreseeable future, new toxophores will be identified through a process of random screening, with natural products representing a rich source of fungicide leads. Progress is being made in the development of high-throughput screens comprised of target enzyme sites or cell-based assays; these techniques will improve the probability of discovery. Following the identification of suitable leads, biorational design is used to optimize specific properties. In vivo glasshouse screens and field trials are expected to remain the dominant methods for characterizing new compounds. Low toxicity to humans and wildlife, low environmental impact, low residues in food, and compatibility with integrated pest management (IPM) programs are increasingly important considerations in the selection of fungicides for development.

Journal Article↗
PubMed1996

Comparative fungicidal activity of a new quaternary ammonium salt, N-alkyl-N-2-hydroxyethyl-N,N-dimethylammonium butyl phosphate and commonly used disinfectants.

We synthesized a new quaternary ammonium salt, N-alkyl-N-2-hydroxyethyl-N, N-dimethylammonium butyl phosphate (ABP) that does not precipitate in the presence of anionic surfactants by incorporating a paired butyl phosphate anion into cationic surfactants. ABP showed much greater bactericidal activities and antirusting effects than benzalkonium chloride (BAC). In this study, the fungicidal effects of ABP were evaluated in comparison with common disinfectants [BAC, chlorhexidine digluconate (CHX) and alkyldiaminoethylglycine hydrochloride (ADE)]. Fungicidal effects were evaluated in 10 strains of 6 fungal species, namely, 3 Candida albicans, 2 Candida tropicalis, 1 Candida parapsilosis, 1 Aspergillus niger, 2 Aspergillus terreus, and 1 Trichophyton rubrum. ABP and BAC showed the same effects on 2 C. tropicalis and C. parapsilosis, and similar effects on 3 C. albicans, with slight differences among the strains. ABP showed quick fungicidal effects against A. niger and 2 A. terreus of molds in 30 min at 0.1% and in 15 min at 0.2 and 0.4%, but BAC showed slow effects against A. niger at 1 h and 2 A. terreus at 30 min at 0.2 and 0.4%, respectively. There is one factor, which may have caused this difference: the former had a butyl phosphate anion and the latter had a chloride anion as a counter ion. BAC, CHX and ADE needed 24h to cause notable effects on A. niger at 0.1% and 1 h at 0.2%. The new synthetic anti-rust ABP is considered to have sufficient fungicidal effects that are comparable to those of BAC, CHX and ADE.

Disinfectants↗
PubMed1991

[Antifungal and fungicidal activities of tea extract and catechin against Trichophyton].

We examined tea extract, (-) epigallocatechin gallate (EGCg) and theaflavin digallate (TF3) for their antifungal and fungicidal activities against Trichophyton mentagrophytes, T. rubrum, Candida albicans and Cryptococcus neoformans. Tea extract (2.5%) inhibited completely the growth of both T. mentagrophytes and T. rubrum. EGCg at 2.5 mg/ml failed to inhibit their growth, whereas TF3 at 0.5 mg/ml inhibited the growth. EGCg (1mg/ml) showed no fungicidal activity against Trichophyton. TF3 (1mg/ml) killed Trichophyton by a long time contact (72-96 hrs). Tea extract showed a fungicidal activity against Trichophyton in a dose- and contact time-dependent manner. It did not inhibit the growth of C. albicans, but at a high concentration, inhibited slightly the growth of C. neoformans. It had no fungicidal activity against C. albicans or C. neoformans.

Antifungal Agents↗
PubMed1987

[Functional criteria for the differentiation of leukemic cells. II. The fungicidal activity of the blast cells from patients with acute monoblastic leukemia].

The studies in the present work are a continuation of the previous studies of the author's on the functional activity of leukosis cells and discuss their fungicidal activity versus Candida albicans. Blast cells from 22 patients with various clinical-morphological forms of acute leukosis were studied. It has been concluded from the results obtained that leukosis cells of monoblast type in acute myelomonoblast (M4) and monoblast (M5) leukosis are able to lyse Candida albicans, the value of their fungicidal activity being lower than that of mature monocytes from peripheral blood of healthy subjects. The fungicidal activity is observed in leukosis cells from patients with promyelocyte (M3) leukosis. The authors propose the fungicidal activity of leukosis cells to be used as an additional, functional criterium in the differentiation of their type.

Blood Bactericidal Activity↗
PubMed2001

Famoxadone: the discovery and optimisation of a new agricultural fungicide.

Famoxadone (3-anilino-5-methyl-5-(4-phenoxyphenyl)-1,3-oxazolidine-2,4-dione), is a new agricultural fungicide recently commercialized by DuPont under the trade name Famoxate. Famoxadone is a member of a new class of oxazolidinone fungicides that demonstrate excellent control of plant pathogens in the Ascomycete, Basidiomycete, and Oomycete classes that infect grapes, cereals, tomatoes, potatoes and other crops. DuPont's entry into the oxazolidinone area resulted from the procurement of 5-methyl-5-phenyl-3-phenylamino-2-thioxo-4-oxazolidinone (1) from Professor Detlef Geffken, then at the University of Bonn. An extensive analog program was initiated immediately after the fungicidal activity of 1 was discovered through routine greenhouse testing. The discovery program in the oxazolidinone area eventually culminated in the advancement of famoxadone to commercial development in the early 1990s. The synthesis of various oxazolidinone ring systems and the development of the structure-activity relationships that led to the discovery of famoxadone are described.

Animals↗
PubMed1996

Effect of some fungicides on extracellular enzymes of Sclerotium rolfsii sacc.

The effect of four fungicides on rot of cocoyam tubers, vegetative growth and extracelluar enzymes of the pathogen was investigated. At 200 ppm concentration, rot was completely prevented by Dithane M45. Benomyl and Iprodione in tubers of Xanthosoma sagittifolium. There was better protection by the fungicides for Cocoyam tubers treated with fungicides before spraying with hyphal suspension than those sprayed first with hyphal suspension of Sclerotium rolfsii sacc. At 600 ppm, Benomyl and Iprodione appreciably inhibited mycelial growth of the pathogen by 100% and 80.2% respectively. Both in vitro polygalacturonase and Cx-cellulase of the pathogen were inhibited by the Iprodione and Benomyl unlike Dithane M45 and Cupravit.

Cellulase↗
PubMed2006

Metrafenone: studies on the mode of action of a novel cereal powdery mildew fungicide.

Powdery mildew fungi are among the major pathogens causing diseases of cereals in the world. The mode of action of a novel systemic benzophenone fungicide, metrafenone, which is based on a precursor that is discussed in the preceding paper, has been analysed on the powdery mildew fungi of barley (Blumeria graminis Speer f. sp. hordei Marchal) and wheat (Blumeria graminis Speer f. sp. tritici Marchal). Preventive treatments reduced germination and blocked development beyond formation of appressoria, which penetrated less often. Moreover, metrafenone turned out to be an efficient curative fungicide, which rapidly affected fungal survival at low concentrations. The fungicide induced swelling, bursting and collapse of hyphal tips, resulting in the release of globules of cytoplasm. Bifurcation of hyphal tips, secondary appressoria and hyperbranching were also frequently observed. A histochemical analysis showed that metrafenone caused disruption of the apical actin cap and apical vesicle transport as well as weakening of the cell wall at hyphal tips. Finally, metrafenone strongly reduced sporulation. Reduced sporulation was associated with malformation of conidiophores that showed irregular septation, multinucleate cells and delocalisation of actin. Microtubules appeared to be only secondarily affected in metrafenone-treated B. graminis. The results suggest that the mode of action of metrafenone interferes with hyphal morphogenesis, polarised hyphal growth and the establishment and maintenance of cell polarity. Metrafenone likely disturbs a pathway regulating organisation of the actin cytoskeleton.

Ascomycota↗
PubMed2006

Degradation of anilinopyrimidine fungicides photoinduced by iron(III)-polycarboxylate complexes.

The photoinduced degradation of three anilinopyrimidine fungicides (cyprodinil, pyrimethanil and mepanipyrim) by Fe(III)-polycarboxylate complexes in aqueous solution was investigated. A photochemical redox reaction of Fe(III) complexes of oxalate and citrate occurs during irradiation (simulating sunlight) and is an important source of Fe(II) and a series of oxidants such as H2O2 and O radicals. The mechanism involves the formation of polycarboxylate radicals and/or carbon-centred radicals derived from decarboxylation, whereas the contribution of Fe(OH)2+ to O radical formation is negligible. The attack of O radicals on the fungicide molecules produces numerous photodegradation products, which were identified by means of LC-ES-MS and turned out to be mono- or dihydroxylated derivatives of the active ingredients, except for 2-amino-4,6-dimethylpyrimidine, which is only formed by pyrimethanil. The half-lives of the active ingredients, when submitted to irradiation in the presence of iron(III)-polycarboxylate complexes, were estimated to vary between 28 and 79 min (photodegradation rates in the same conditions: mepanipyrim > cyprodinil > pyrimethanil), and photodegradation is slower in citrate than in oxalate solutions. Photoproducts and their kinetics of formation are very similar for the three fungicides. The OH substitution involves the aromatic and the heterocyclic ring and the nitrogen bridge between the two rings, except for mepanipyrim when the hydroxylation also involves the propynylic side chain.

Citric Acid↗
PubMed2002

Biological properties of the novel fungicide cyazofamid against Phytophthora infestans on tomato and Pseudoperonospora cubensis on cucumber.

Cyazofamid (ISO proposed common name), 4-chloro-2-cyano-N,N-dimethyl-5-p-tolylimidazole-1-sulfonamide is a novel fungicide exhibiting specific activity against diseases caused by Oomycetes. In tests, cyazofamid at 0.4-1.6 mg litre-1 exhibited excellent preventative activity against Phytophthora infestans on tomato and Pseudoperonospora cubensis on cucumber. Minimum inhibitory concentrations of cyazofamid against both diseases were over 63 times lower than those of mancozeb and at least 16 times lower than those of metalaxyl. Cyazofamid at 1.6-25 mg litre-1 exhibited not only preventative activity, but also stable residual activity and rainfastness. Cyazofamid at 6.3 mg litre-1 reduced zoosporangia formation of P infestans and P cubensis on host plants by 100 and 94% respectively. Cyazofamid also exhibited translaminar and curative activity. Cyazofamid has a new mode of action for fungicides and exhibits no cross-resistance with other currently registered and commonly used fungicides. These properties lead to a high level control by cyazofamid in field.

Alanine↗
PubMed2003

Modulators of membrane drug transporters potentiate the activity of the DMI fungicide oxpoconazole against Botrytis cinerea.

Modulators known to reduce multidrug resistance in tumour cells were tested for their potency to synergize the fungitoxic activity of the fungicide oxpoconazole, a sterol demethylation inhibitor (DMI), against Botrytis cinerea Pers. Chlorpromazine, a phenothiazine compound known as a calmodulin antagonist, appeared the most potent compound. Tacrolimus, a macrolide compound with immunosuppressive activity, was also active. The synergism of chlorpromazine negatively correlated with the sensitivity of the parent strain and mutants of B. cinerea. The synergism was highest in a mutant that overexpressed the ATP-binding cassette transporter BcatrD, known to transport DMI fungicides such as oxpoconazole. The synergism of chlorpromazine positively correlated with its potency to enhance the accumulation of oxpoconazole in BcatrD mutants. These results indicate that chlorpromazine is a modulator of BcatrD activity in B. cinerea and suggest that mixtures of DMI fungicides with modulators may represent a perspective for the development of new resistance management strategies.

Botrytis↗
PubMed2003

A critical evaluation of the role of alternative oxidase in the performance of strobilurin and related fungicides acting at the Qo site of complex III.

Mitochondrial respiration conserves energy by linking NADH oxidation and electron-coupled proton translocation with ATP synthesis, through a core pathway involving three large protein complexes. Strobilurin fungicides block electron flow through one of these complexes (III), and disrupt energy supply. Despite an essential need for ATP throughout fungal disease development, strobilurins are largely preventative; indeed some diseases are not controlled at all, and several pathogens have quickly developed resistance. Target-site variation is not the only cause of these performance difficulties. Alternative oxidase (AOX) is a strobilurin-insensitive terminal oxidase that allows electrons from ubiquinol to bypass Complex III. Its synthesis is constitutive in some fungi but in many others is induced by inhibition of the main pathway. AOX provides a strobilurin-insensitive pathway for oxidation of NADH. Protons are pumped as electrons flow through Complex I, but energy conservation is less efficient than for the full respiratory chain. Salicylhydroxamic acid (SHAM) is a characteristic inhibitor of AOX, and several studies have explored the potentiation of strobilurin activity by SHAM. We present a kinetic-based model which relates changes in the extent of potentiation during different phases of disease development to a changing importance of energy efficiency. The model provides a framework for understanding the varying efficacy of strobilurin fungicides. In many cases, AOX can limit strobilurin effectiveness once an infection is established, but is unable to interfere significantly with strobilurin action during germination. A less stringent demand for energy efficiency during early disease development could lead to insensitivity towards this class of fungicides. This is discussed in relation to Botrytis cinerea, which is often poorly controlled by strobilurins. Mutations with a similar effect may explain evidence implicating AOX in resistance development in normally well-controlled plant pathogens, such as Venturia inaequalis.

Drug Resistance, Fungal↗
PubMed2003

Persistence of the fungicides thiabendazole, carbendazim and prochloraz-Mn in mushroom casing soil.

The persistence of the fungicides thiabendazole, carbendazim and prochloraz-Mn in mushroom casing soil was determined following their application at rates commonly used in the UK mushroom industry. Following drench applications, the concentration of all active ingredients was always higher in the top half of the casing soil layer than in with the bottom half. When carbendazim and prochloraz-Mn were applied using half the recommended volume of water per unit area, there was a tendency for carbendazim concentrations to be even higher in the top half of the casing soil, compared with the standard treatment, while concentrations of prochloraz-Mn were similar, irrespective of the volume of water used. Carbendazim and prochloraz-Mn concentrations in the top half of the casing layer decreased to < or = 13 mg kg(-1) by day 28/29, following different applications, whereas the thiabendazole concentration was consistently high during the course of the crop, being < or = 83 mg kg(-1) at day 31. Fungicides that do not persist at high concentrations in mushroom casing soil for the duration of the crop may not give good control of mushroom pathogens, particularly if the fungicide concentration falls to a level which is close to the EC50 value.

Agaricales↗
PubMed2003

Multiple mechanisms account for variation in base-line sensitivity to azole fungicides in field isolates of Mycosphaerella graminicola.

Molecular mechanisms that account for variation in base-line sensitivity to azole fungicides were examined in a collection of twenty field isolates, collected in France and Germany, of the wheat pathogen Mycosphaerella graminicola (Fuckel) Schroeter. The isolates tested represent the wide baseline sensitivity to the azole fungicide tebuconazole described previously. The isolates were cross-sensitive to other azoles tested, such as cyproconazole and ketoconazole, but not to unrelated chemicals like cycloheximide, kresoxim-methyl or rhodamine 6G. Progenies from a genetic cross between an isolate with an intermediate and a high sensitivity to azoles displayed a continuous range of phenotypes with respect to cyproconazole sensitivity, indicating that variation in azole sensitivity in this haploid organism is polygenic. The basal level of expression of the ATP-binding cassette transporter genes MgAtr1-MgAtr5 from Mgraminicola significantly varied amongst the isolates tested, but no clear increase in the transcript level of a particular MgAtr gene was found in the less sensitive isolates. Cyproconazole strongly induced expression of MgAtr4, but no correlation between expression levels of this gene and azole sensitivity was observed. One isolate with intermediate sensitivity to azoles over-expressed CYP51, encoding cytochrome P450 sterol 14alpha-demethylase from M graminicola. Isolates with a low or high sensitivity to azoles were tested for accumulation of cyproconazole, but no clear correlation between reduced accumulation of the fungicide in mycelium and sensitivity to azoles was observed. Therefore, differences in accumulation cannot account exclusively for the variation in base-line sensitivity of the isolates to azoles. The results indicate that multiple mechanisms account for differences in base-line sensitivity to azoles in field isolates of M graminicola.

ATP-Binding Cassette Transporters↗
PubMed2004

A mini-bag technique for evaluation of fungicide effects on Trichoderma spp in mushroom compost.

An in vivo technique was developed to observe colonisation of mushroom compost by Trichoderma spp. Isolates of T. harzianum (Th2), T. harzianum (Th1), T. koningii (Tk) and T. viride (Tv) were artificially introduced into compost using a mini-bag system. Wheat grains, colonised by Trichoderma spp, were placed centrally on a layer of compost at the bottom of 1-litre polythene bags which were then filled with 350 g of spawned or un-spawned compost, and partially sealed. After 14 and 21 days incubation at 27 degrees C, the bags were assessed for recovery of Trichoderma from middle and top zones using a needle stab re-isolation technique and a visual colonisation scoring system. Visible green mould contamination, similar to that observed in practice, developed within 21 days. The visual colonisation scoring was reliably related to the re-isolation success. In this evaluation, Trichoderma spp showed considerable differences in their relative abilities to colonise spawned and un-spawned compost, with Th2 isolates being consistently superior to the other isolates of Th1, Tk and Tv in colonising spawned compost. This technique was employed to evaluate the effects of fungicides on the colonisation of mushroom compost by three Trichoderma spp: Th2, Th1 and Tk, using 1-litre and 5-litre mini-bag systems. Aqueous suspensions of benomyl, carbendazim, thiabendazole, prochloraz and prochloraz+carbendazim incorporated into the compost at 50 mg litre(-1), or applied to spawn at 50 mg kg(-1), reduced the colonisation by Trichoderma spp. Prochloraz and prochloraz+carbendazim were superior to benomyl, carbendazim or thiabendazole in reducing compost colonisation by Th2, Th1 and Tk, with Th2 being the most persistent type, capable of colonising treated compost in the presence of all five fungicides. The prochloraz+carbendazim mixture, not normally used in mushroom production, was equal to or better than prochloraz alone. The incidence of green mould colonisation by Th2 was as extensive in the 5-litre compost bags as in the 1-litre bags, but colonisation by Th1 and Tk was more apparent in the 5-litre bags. The in vivo mini-bag evaluations using wheat grain Trichoderma inoculum and needle stab re-isolation procedures proved an efficient method for studying colonisation and screening for effectiveness of fungicides applied to mushroom compost or spawn.

Agaricales↗