Molecular Mode of Action of the Antifungal β-Amino Acid BAY 10-8888

Ziegelbauer, Karl; Babczinski, Peter; Schönfeld, W.

doi:10.1128/aac.42.9.2197

Cited by 53 publications

(25 citation statements)

References 25 publications

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“…While inhibitors of the C. albicans leucine biosynthetic pathway alone would have little utility in vivo since leucine auxotrophs are virulent (Kirsch & Whitney, 1991; Noble & Johnson, 2005), since the toxic effects in ilv2 Δ mutants are likely due to isoleucine and valine starvation, inhibitors of other isoleucine and valine biosynthetic enzymes would likely also be effective. Furthermore, given that isoleucine starvation is also fungicidal and the ilv1 Δ mutant is somewhat attenuated in virulence in C. albicans , any inhibitor targeting an isoleucine-biosynthetic enzyme should have a clinically beneficial interaction with any of the various isoleucyl tRNA synthetase inhibitors currently available with antifungal activity, such as the antibacterial agent mupirocin (Nicholas et al , 1999), or the anticandidal drug BAY 10-8888 (PLD-118) (Ziegelbauer, 1998; Ziegelbauer et al , 1998). Finally, since the growth rate of ilv2 Δ mutants was reduced compared with the wild-type even in the presence of abundant levels of isoleucine and valine, Ilv2p inhibition may not require complete absence of isoleucine and valine from the environment to have a therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2Δ) mutants is influenced by the carbon source and rapamycin

Kingsbury

McCusker

2010

Microbiology

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The isoleucine and valine biosynthetic enzyme acetolactate synthase (Ilv2p) is an attractive antifungal drug target, since the isoleucine and valine biosynthetic pathway is not present in mammals, Saccharomyces cerevisiae ilv2Δ mutants do not survive in vivo, Cryptococcus neoformans ilv2 mutants are avirulent, and both S. cerevisiae and Cr. neoformans ilv2 mutants die upon isoleucine and valine starvation. To further explore the potential of Ilv2p as an antifungal drug target, we disrupted Candida albicans ILV2, and demonstrated that Ca. albicans ilv2Δ mutants were significantly attenuated in virulence, and were also profoundly starvation-cidal, with a greater than 100-fold reduction in viability after only 4 h of isoleucine and valine starvation. As fungicidal starvation would be advantageous for drug design, we explored the basis of the starvation-cidal phenotype in both S. cerevisiae and Ca. albicans ilv2Δ mutants. Since the mutation of ILV1, required for the first step of isoleucine biosynthesis, did not suppress the ilv2Δ starvation-cidal defects in either species, the cidal phenotype was not due to α-ketobutyrate accumulation. We found that starvation for isoleucine alone was more deleterious in Ca. albicans than in S. cerevisiae, and starvation for valine was more deleterious than for isoleucine in both species. Interestingly, while the target of rapamycin (TOR) pathway inhibitor rapamycin further reduced S. cerevisiae ilv2Δ starvation viability, it increased Ca. albicans ilv1Δ and ilv2Δ viability. Furthermore, the recovery from starvation was dependent on the carbon source present during recovery for S. cerevisiae ilv2Δ mutants, reminiscent of isoleucine and valine starvation inducing a viable but non-culturable-like state in this species, while Ca. albicans ilv1Δ and ilv2Δ viability was influenced by the carbon source present during starvation, supporting a role for glucose wasting in the Ca. albicans cidal phenotype.

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Section: Discussionmentioning

confidence: 99%

Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2Δ) mutants is influenced by the carbon source and rapamycin

Kingsbury

McCusker

2010

Microbiology

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“…They serve as artificial substrate and get accumulated in fungal cells by amino acid permease. Once inside the cell 44 and 45 also inhibit fungal protein biosynthesis by inhibiting isoleucyl-tRNA synthase [110][111][112].…”

Section: Isoleucyl-trna Synthasementioning

confidence: 99%

Current Advances in Antifungal Targets and Drug Development

Sundriyal¹,

Sharma²,

Jain

2006

CMC

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Fungi are one of the most neglected pathogens apparent from the fact that the Amphotericin B, a polyene antibiotic, discovered way back in 1956 is still used as a 'gold standard' for antifungal therapy. Past two decades have witnessed a dramatic rise in the incidences of life threatening systemic fungal infections. This can be ascribed to the increase in the number of immuno-compromised patients due to rise in HIV infected population, cancer chemotherapy and indiscriminate use of antibiotics. Majority of clinically used antifungals suffer from various drawbacks in terms of toxicity, efficacy and cost, and their frequent use has led to the emergence of resistant strains. Hence, there is a great demand for novel antifungals belonging to wide range of structural classes, selectively acting on novel targets with fewer side effects. This article aims at reviewing recent efforts made towards discovering novel antifungal drug targets and investigational molecules acting on them.

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“…The growth inhibitory effects of the agent were reversed by intracellular L-isoleucine. PLD-118 inhibiteed isoleucyl in a concentration-dependent manner, with a K i of 1 mM obtained, suggesting that the interaction of the agent with its substrate is not very specific (13,20). Further analysis of the mechanism of action of PLD-118 revealed that accumulation of the agent into selected C. albicans mutants was reduced while isoleucyl-tRNA synthetase activity was increased.…”

Section: Introductionmentioning

confidence: 99%

“…1). Cyclic β-amino acids are one class of potent antifungals that appear to a have a dual mode of action: inhibition of protein synthesis after concentrative uptake and interference with self-regulatory mechanisms of amino acid metabolism (12,13). Cispentacin is a naturally occurring cyclic β-amino acid with potent in vitro and in vivo anti-Candida activity including inhibitory activity against C. albicans, Candida krusei and Candida tropicalis (MIC range for Candida spp.…”

Section: Introductionmentioning

confidence: 99%

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PLD-118

Sorbera¹,

Castañer²,

Bozzo³

2002

Drugs of the Future

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SynthesisPLD-18 can be obtained by three related ways: 1) Basic hydrolysis of cis-4-methylenecyclopentane-1,2-dicarboxylic acid diethyl ester (I) with LiOH gives the free acid (II), which by refluxing with propionic anhydride yields the cyclic anhydride (III). Rearrangement using trimethylsilyl azide in dioxane at 80 °C produces the oxazinedione (IV), which is hydrolyzed to (±)-cis-2-amino-4-methylenecyclopentane-1-carboxylic acid ethyl ester (V) by means of acetyl chloride in EtOH. Further hydrolysis of ester (V) with aqueous HCl provides the racemic amino acid (VI), which is coupled with N-(9-fluorenylmethoxycarbonyl)succinimide (VII) to afford the Fmocamino acid (VIII). Racemic (VIII) is resolved by treatment with (+)-(R)-1-phenylethylamine (IX) and crystallization of the resulting salt (X) in EtOH/methyl tert-butyl ether. Finally, acidification of salt (X) and extraction of the (1R,2S)-free acid, followed by removal of the Fmoc group with liquid ammonia, provides PLD-118 isolated as its hydrochloride salt (1). Scheme 1.2) Hydrolysis of diester (I) with KOH in water/EtOH at 55 °C gives the dicarboxylic acid (II), which is subjected to cyclization by refluxing with propionic anhydride to provide anhydride (III). Cyclic anhydride (III) is opened with allyl alcohol (XI) in diethyl ether in the presence of ()-quinine as asymmetric inducer to yield ()-1,2-cis-4-methylenecyclopentane-1,2-dicarboxylic acid monoallyl ester ()-(XII), which is then converted into the amide derivative ()-(XIII) by activation of the carboxylic acid group with isobutyl chloroformate in ethyl acetate in the presence of N-ethylmorpholine at 6 °C, followed by reaction with aqueous ammonia. Removal of the allyl group of ()-(XIII) with triphenylphosphine, tetrakis(triphenylphosphine)palladium and 2-ethylhexanoic acid sodium salt in ethyl acetate affords ()-1,2-cis-2-(aminocarbonyl)-4-methylenecyclopentane-1-carboxylic acid sodium salt ()-(XIV). Compound ()-(XIV) is subjected to a Hofmann rearrangement with KOH and KOCl in water to provide a crude aqueous solution containing PLD-118, which is finally purified by protection of the free amine group with

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Molecular Mode of Action of the Antifungal β-Amino Acid BAY 10-8888

Cited by 53 publications

References 25 publications

Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2Δ) mutants is influenced by the carbon source and rapamycin

Cytocidal amino acid starvation of Saccharomyces cerevisiae and Candida albicans acetolactate synthase (ilv2Δ) mutants is influenced by the carbon source and rapamycin

Current Advances in Antifungal Targets and Drug Development

PLD-118

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