A preliminary study of<i>in vitro</i>antibiotic activity of saperconazole and other azoles on<i>Paracoccidioides brasiliensis</i>

San-Blas, Gioconda; Calcagno, A. M.; San-Blas, Felipe

doi:10.1080/02681219380000201

Cited by 15 publications

(19 citation statements)

References 13 publications

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“…Naturally, our results can be compared only with those obtained by other authors with reference to the yeast phase of P. brasiliensis. Our MIC data for itraconazole are similar to those reported by others (8,29), which collectively show that this fungus is extremely sensitive to this drug. No significant difference was observed between the MICs obtained for isolates from patients and those obtained for environmental isolates: Pb-262 (isolated from dry dog food in Minas Gerais, Brazil), Pb-Pinguim (isolated from penguin feces from the Uruguayan Antarctic), and Pb-Tatu (isolated from the intestines of an armadillo captured in the region of Pará, Brazil).…”

Section: Resultssupporting

confidence: 79%

“…In vitro susceptibilities of P. brasiliensis to antifungal drugs have been determined by several investigators (7,8,11,14,23,29). Some of these previous studies (8, 14, 29) compared susceptibilities in the yeast phase and the mycelial phase of P. brasiliensis, finding small differences that were attributed to variations in the lipid composition of the two morphological phases.…”

Section: Resultsmentioning

confidence: 99%

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In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

et al. 2002

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In vitro, terbinafine is highly active against a broad spectrum of pathogenic fungi. We evaluated the activities of terbinafine and itraconazole against 31 isolates of Paracoccidioides brasiliensis. The tests were conducted by using a broth macrodilution procedure. MICs, in micrograms per milliliter, were as follows: terbinafine, 0.015 to 1.0 (geometric mean, 0.1188); itraconazole, 0.007 to 0.5 (geometric mean, 0.03165). The usual therapy for paracoccidioidomycosis is sulfonamides, amphotericin B, and azole derivatives (ketoconazole, itraconazole, and fluconazole). In comparison to amphotericin B, azole derivatives allow shorter treatment courses, can be administered orally, and are equally effective. Itraconazole has as high efficacy as ketoconazole, but with superior tolerance. It is the current drug of choice for treatment of paracoccidioidomycosis. The data obtained in this study indicate that terbinafine is active against P. brasiliensis in vitro and suggest that this allylamine can be considered a new option as drug therapy for paracoccidioidomycosis.Paracoccidioidomycosis, caused by the dimorphic fungus Paracoccidioides brasiliensis, is a systemic human mycosis geographically confined to Latin America (1,25,28). In vitro tests of the susceptibility of P. brasiliensis to antimycotic drugs have been scarce, and the results have not always been consistent; the discrepancies are attributed to the diversity of techniques employed in such studies (7,8,10,11,22,28).Organisms belonging to the kingdom Fungi share eukaryotic characteristics with their human host cells, implying similarities in biochemistry and physiology that limit therapeutics. Therefore, when systemic administration of drugs is required for deep human mycoses, few compounds are sufficiently selective (12). Compounds currently used in the control of infection caused by P. brasiliensis include amphotericin B, trimethoprimsulfamethoxazole, and azole derivatives (26). Unfortunately, amphotericin B has been associated with substantial toxicity, while trimethoprim-sulfamethoxazole has been associated with relapses. Thus, in many clinical situations, the azole derivatives present the best therapeutic option for control of paracoccidioidomycosis (17, 18).Owing to the fact that itraconazole, among the azoles, permits shorter treatment courses and has been shown to be more effective, we decided to compare this drug with the antifungal agent terbinafine, which operates by interfering with the ergosterol biosynthetic pathway and has shown MICs similar to those of itraconazole for filamentous fungi in in vitro studies (10,15). Thus, we aim to determine whether terbinafine might have a role in the management of infections caused by P. brasiliensis. MATERIALS AND METHODSFungal strains and culture conditions. Thirty-one isolates of the P. brasiliensis yeast form, including clinical, environmental, and animal isolates, were examined in this study. Samples consisted of 28 strains isolated from humans, 1 from penguin feces, 1 from dog food, and 1 from an armadillo....

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Section: Resultssupporting

confidence: 79%

Section: Resultsmentioning

confidence: 99%

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

et al. 2002

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“…In C. albicans, enzymic defects in ergosterol-deficient (erg) mutants lead to the Azoles (ketoconazole, itraconazole and saperconazole) (San-Blas et al, 1993a) are very effective growth inhibitors against P. brasiliensis, indicating that the fungus requires specific 4,14-desmethyl sterols of the ergosta type for growth. The neutral lipid fraction of P. brasiliensis, Y phase, contained ergosta-S,22-dien-3p-01 (82%) as the main free sterol, plus much lower amounts of lanosterol (12%) and ergosterol (6%).…”

Section: Resultsmentioning

confidence: 99%

“…Membrane disturbance leads to the deterioration of fungal structures, among them the cell wall, whose synthesis depends on the correct performance of the enzymic machinery located in the plasma membrane (San-Blas & San-Blas, 1994). Ajoene is also capable of blocking the thermally induced transition from the M to the Y phase (San-Blas et al, 1993b), an effect that together with the already mentioned effect on growth, may be of interest in therapy, since the transition process is the first requirement for the establishment of paracoccidioidomycosis in the host (Lacaz, 1994).…”

Section: Introductionmentioning

confidence: 99%

Paracoccidioides brasiliensis by ajoene is associated with blockade of phosphatidylcholine biosynthesis

et al. 1997

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In Paracoccidioides brasiliensis, a dimorphic fungus pathogenic for humans, no significant differences were observed in the phospholipid species of both morphological phases. The species observed were phosphatidylcholine (PC, 30-40 O h ) , p hosp hat idy let hanolami ne (PE, 27-28 O h ) , phosp hat id y lser i ne (16-19%), phosphatidylinositol (1347%) and sphingomyelin (3-50' 0). The main fatty acids found in the yeast (Y) phase were palmitate (56%), linoleate (18%) and oleate (15%), while linoleate predominated (61 YO) in the mycelial (M) phase, followed by palmitate (27 YO) and oleate (7 YO). In the Y phase the main free sterol was ergosta=5,22=dien=3/%ol (82 YO) plus some lanosterol (12 YO) and ergosterol (6%), while in the M phase, the latter predominated (88%), followed by low levels of ergosta-5,22-dien-3/%ol (12 YO). Ajoene [(€,2)-4,5,9-trithiadodeca-l,6,11-triene 9-oxide], a platelet aggregation inhibitor derived from garlic, induced alterations in phospholipid and fatty acid proportions such that PC was reduced to about 18% in both phases and PE increased to 38% (Y phase) or 44% (M phase), suggesting inhibition of PC synthesis. Ajoene also reduced saturated fatty acids (16:O and 18:O) from 67 to 35% in the Y phase, with a corresponding increase in the unsaturated components. This effect was not seen in the M phase.

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“…This fungus is a thermally dimorphic fungus, the causative agent of paracoccidioidomycosis, a prevalent human systemic mycosis in Latin America where it is geographically constrained. P. brasiliensis is sensitive to sterol biosynthesis inhibitors, such as ketoconazole, itraconazole, and saperconazole (9), and is also affected by ajoene, a derivative of allicin, extracted from garlic (8). In the search for new antifungal agents, we chose to test AZA-1, AZA-2, and AZA-3 in P. brasiliensis Y phase.…”

mentioning

confidence: 99%

S -Adenosyl- l -Methionine Inhibitors Δ ²⁴ -Sterol Methyltransferase and Δ ²⁴⁽²⁸⁾ -Sterol Methylreductase as Possible Agents against Paracoccidioides brasiliensis

Visbal

Álvarez²,

Moreno

et al. 2003

Antimicrob Agents Chemother

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We studied the antiproliferative effects of three azasterol analogs [piperidyl-2-yl-5␣-pregnan-3␤,20(R)-diol (AZA-1), 22-piperidin-2-yl-pregnan-22(S),3␤-diol (AZA-2), and 22-piperidin-3-yl-pregnan-22(S),3␤-diol (AZA-3)] and their effects on the lipid composition of the pathogenic yeastlike phase of the dimorphic fungus Paracoccidioides brasiliensis. Inhibition was 100% for AZA-1 at 5 M, 62% for AZA-2 at 10 M, and 100% for AZA-3 at 0.5 M. The analogs inhibited different stages of the sterol biosynthesis pathway.Membrane sterol biosynthesis is one of the few areas of difference in primary metabolism between mammals and other eukaryotes, such as plants, fungi, and protozoa. While mammals synthesize C 27 cholestane-based members of the steroid family, pathogenic fungi, protozoa, and plants require the presence of endogenous sterols (typically ergosterol and 24-alkyl analogs) which act as essential growth factors for these organisms (4, 12). The enzyme responsible for the addition of these alkyl groups to carbon C-24 and for the regulation of carbon flow in the sterol pathway is the ⌬ 24 -sterol methyltransferase (SMT) (6). The critical role of this enzyme has stimulated considerable interest in the rational design of SMT inhibitors for potential clinical or agrochemical use as antifungal agents (1, 2, 12). Several sterol analogues behave as antiproliferative agents against fungi, yeast, protozoa, and plants in vitro (1,2,8,11,12). One sterol analogue, 20-piperidyl-2-yl-5␣-pregnan-3␤,20(R)-diol (AZA-1) has been reported to be an SMT inhibitor in the protozoan species Trypanosoma cruzi, Leishmania donovani, and the fungus Pneumocystis carinii (5,11,12). The antiproliferative effect of AZA-1 against these organisms coincided with the depletion of 24-alkyl-sterols and their complete replacement by ⌬ 24 -cholesta-type sterols. Recently, Atencio et al. (1) studied the molecular parameters of AZA-1 and its N-methyl derivative and established some structureactivity correlation. The information obtained from these compounds and the steric-electric plug model proposed by Nes (6) has allowed the design and synthesis of two new azasterols, 22-piperidin-2-yl-pregnan-22(S),3␤-diol (AZA-2) and 22-piperidin-3-yl-pregnan-22(S),3␤-diol (AZA-3) (Fig. 1) (Visbal et al., submitted).To explore the potential use of these new drugs, we studied the effects of azasterol analogs AZA-1, AZA-2, and AZA-3 on growth and sterol profile in the pathogenic yeastlike (Y) phase of Paracoccidioides brasiliensis. This fungus is a thermally dimorphic fungus, the causative agent of paracoccidioidomycosis, a prevalent human systemic mycosis in Latin America where it is geographically constrained. P. brasiliensis is sensitive to sterol biosynthesis inhibitors, such as ketoconazole, itraconazole, and saperconazole (9), and is also affected by ajoene, a derivative of allicin, extracted from garlic (8). In the search for new antifungal agents, we chose to test AZA-1, AZA-2, and AZA-3 in P. brasiliensis Y phase.Experiments were performed as previously reported...

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A preliminary study ofin vitroantibiotic activity of saperconazole and other azoles onParacoccidioides brasiliensis

Cited by 15 publications

References 13 publications

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

Paracoccidioides brasiliensis by ajoene is associated with blockade of phosphatidylcholine biosynthesis

S -Adenosyl- l -Methionine Inhibitors Δ ²⁴ -Sterol Methyltransferase and Δ ²⁴⁽²⁸⁾ -Sterol Methylreductase as Possible Agents against Paracoccidioides brasiliensis

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A preliminary study ofin vitroantibiotic activity of saperconazole and other azoles onParacoccidioides brasiliensis

Cited by 15 publications

References 13 publications

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

In Vitro Comparison of Activities of Terbinafine and Itraconazole against Paracoccidioides brasiliensis

Paracoccidioides brasiliensis by ajoene is associated with blockade of phosphatidylcholine biosynthesis

S -Adenosyl- l -Methionine Inhibitors Δ 24 -Sterol Methyltransferase and Δ 24(28) -Sterol Methylreductase as Possible Agents against Paracoccidioides brasiliensis

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S -Adenosyl- l -Methionine Inhibitors Δ ²⁴ -Sterol Methyltransferase and Δ ²⁴⁽²⁸⁾ -Sterol Methylreductase as Possible Agents against Paracoccidioides brasiliensis