Antifungal Drug Discovery: Old Drugs, New Tools

Backer, Marianne D. De; Luyten, Walter; Bossche, Hugo F. Vanden

doi:10.1007/978-1-59259-172-5_12

Cited by 3 publications

(4 citation statements)

References 158 publications

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“…AZA-3 produced a major antiproliferative effect on P. brasiliensis that was due to SMT inhibition, as deduced from the important accumulation of lanosterol (compound A) recorded in this case. This contrasts with the reported effect of ketoconazole (3) on the accumulation of 24-methylene dihydrolanosterol (compound B) through the inhibition of the cytochrome P-450-dependent C14␣-demethylase (3).…”

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confidence: 84%

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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

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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confidence: 84%

“…On the other hand, AZA-3 was the most powerful drug, as a concentration of 0.5 M was able to completely inhibit fungal growth. All three drugs were fungistatic rather than fungicidal, as treated cells resuspended in fresh medium reinitiated normal growth (data not shown), an effect also observed for azoles (3).…”

mentioning

confidence: 64%

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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“…However, the metabolic pathway to the synthesis of sterols also involves differentiated steps in both fungal and mammal organisms, that may be used for blocking growth of the former without affecting the latter. One such step refers to the sterol C-methylations catalyzed by the enzyme (S)-adenosyl-L-methionine: ∆ 24 _ sterol methyl transferase (SMT) [50][51][52][53][54]. This reaction controls electrophylic alkylations, a step of outmost importance in C-C bond formation of natural products.…”

Section: ∆ 24 _ Sterol Methyl Transferase (Smt) In the Synthesis Of Mmentioning

confidence: 99%

“…While mammals synthesize C 27 cholestane-based members of the steroid family, pathogenic fungi, protozoa and plants require the presence of endogenous sterols C 28 -C 29 (typically ergosterol and 24-alkyl analogs) which act as essential growth factors for these organisms (Fig. 2) [50][51][52][53][54]. 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 methyl transferase (SMT) (Fig.…”

Section: ∆ 24 _ Sterol Methyl Transferase (Smt) In the Synthesis Of Mmentioning

confidence: 99%

Paracoccidioides brasiliensis, Paracoccidioidomycosis, and Antifungal Antibiotics

Visbal¹,

San-Blas²,

Murgich³

et al. 2005

CDTID

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Paracoccidioides brasiliensis is the causative agent of paracoccidioidomycosis (PCM), a human systemic, chronic and progressive mycosis. Preferred antifungals are sulfamethoxazol-trimethoprim, itraconazole, amphotericin B. Treatment is lengthy, the drugs may have undesirable side effects, and some are costly. Occasional resistant strains have been reported. Therefore, the search for more selective and efficient antifungals to treat this and other mycoses continues. Ajoene, chemically derived from garlic, behaves as an antifungal agent against P. brasiliensis and other fungi. Its antiproliferative effects in P. brasiliensis are associated with a reduction of phosphatidyl choline, a concomitant increase in its precursor phosphatidyl ethanolamine, and a large increase in unsaturated fatty acids in the pathogenic yeast phase. The sterol biosynthetic pathway has been largely studied for the search of antifungals. Azoles and allilamines act on differents steps of this pathway. However, they may interfere with similar steps in the host. Hence, the search for drugs that may act on more specific steps is ongoing. One such step focuses on the sterol C-methylations catalyzed by the enzyme (S)-adenosyl-L-methionine: Delta(24) - sterol methyl transferase (SMT). SMT inhibitors such as azasterols and derivatives (AZA1, AZA2, AZA3) have proven highly effective as antiproliferative agents against protozoa and some fungi, among them, P. brasiliensis. Their chemical synthesis and structure, and their molecular electrostatic potential are discussed in order to understand their mechanism of action, and derive rationally designed improvements on these molecules, that would favour a higher efficacy and selectivity.

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Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

Kanagasabai

Zhou

Liu

et al. 2004

Lipids

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The sterol substrate analog 25-thialanosterol and its corresponding sulfonium salt were evaluated for their ability to serve as antifungal agents and to inhibit sterol methyltransferase (SMT) activity in Candida albicans. Both compounds inhibited cell proliferation, were fungistatic, interrupted the yeast-like-form to germ-tube-form transition, and resulted in the accumulation of zymosterol and related delta24-sterols concurrent with a decrease in ergosterol, as was expected for the specific inhibition of SMT activity. Feedback on sterol synthesis was evidenced by elevated levels of cellular sterols in treated vs. control cultures. However, neither farnesol nor squalene accumulated in significant amounts in treated cultures, suggesting that carbon flux is channeled from the isoprenoid pathway to the sterol pathway with minor interruption or redirection until blockage at the C-methylation step. Activity assays using solubilized C. albicans SMT confirmed the inhibitors impair SMT action. Kinetic analysis indicated that 25-thialanosterol inhibited SMT with the properties of a time-dependent mechanism-based inactivator Ki of 5 microM and apparent kinact of 0.013 min(-1), whereas the corresponding sulfonium salt was a reversible-type transition state analog exhibiting a Ki of 20 nM. The results are interpreted to imply changes in ergosterol homeostasis as influenced by SMT activity can control growth and the morphological transition in C. albicans, possibly affecting disease development.

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Antifungal Drug Discovery: Old Drugs, New Tools

Cited by 3 publications

References 158 publications

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

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

Paracoccidioides brasiliensis, Paracoccidioidomycosis, and Antifungal Antibiotics

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

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Antifungal Drug Discovery: Old Drugs, New Tools

Cited by 3 publications

References 158 publications

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

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

Paracoccidioides brasiliensis, Paracoccidioidomycosis, and Antifungal Antibiotics

Disruption of ergosterol biosynthesis, growth, and the morphological transition in Candida albicans by sterol methyltransferase inhibitors containing sulfur at C‐25 in the sterol side chain

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Product

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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

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