A case of cutaneous Scedosporium apiospermum infection in a patient on a janus kinase inhibitor.

Scedosporium apiospermum is a mold that is usually found in soil and polluted water, but has also been linked to contaminated ambient air in hospitals. This fungus typically behaves as a rare opportunistic pathogen affecting immunocompromised patients in whom disseminated disease can readily occur, causing shock and multiorgan failure. We report the first case of cutaneous Scedosporium apiospermum infection in a patient with rheumatoid arthritis treated with a Janus kinase inhibitor. We also reviewed other cutaneous manifestations of Scedosporium apiospermum reported between 2003 and 2022.

Discovery of small-molecule inhibitors of tyrosinase.

To identify novel inhibitors of tyrosinase, a fluorescent assay was developed which is suitable for high-throughput screening. In the assay, oxidation of the substrate by tyrosinase leads to the release of a fluorescent coumarin. Several small molecules were identified that inhibited mushroom tyrosinase in vitro and human tyrosinase in cell culture. These compounds may represent lead structures for therapies targeted at disorders of hyperpigmentation.

Reactivity of reduced [2Fe-2S] ferredoxins parallels host susceptibility to nitroimidazoles.

The kinetics of the electron transfer reaction between reduced [2Fe-2S] ferredoxins and select nitroimidazole antimicrobial agents is reported. The ferredoxins from the protozoan Trichomonas vaginalis and the cyanobacterium Anabaena sp. strain 7120 were studied because they are the proximal electron donors to nitroimidazoles in these two organisms with significantly different nitroimidazole susceptibilities. The rates of electron transfer from Anabaena ferredoxin to all nitroimidazoles were 1 to 2 orders of magnitude lower than for T. vaginalis ferredoxin. Quantitative structure-activity analysis of the kinetic data showed that the size of the alkyl substituent on the N-1 position of the imidazole ring strongly influenced the magnitude of the electron transfer rate constant. This implies that the distance between the iron-sulfur cluster and the nitro group of the imidazole is the critical variable in determining the rate of electron transfer. A correlation between the magnitude of the one-electron transfer rate constant with the susceptibility of the host organism to the cytotoxic effects of nitroimidazoles was also discovered. These results demonstrate that reductive activation is the most crucial step in determining the toxicity of nitroimidazoles.

The crystal structure of Trichomonas vaginalis ferredoxin provides insight into metronidazole activation.

Crystallographic studies revealing the three-dimensional structure of the oxidized form of the [2Fe-2S] ferredoxin from Trichomonas vaginalis (TvFd) are presented. TvFd, a member of the hydrogenosomal class of ferredoxins, possesses a unique combination of redox and spectroscopic properties, and is believed to be the biological molecule that activates the drug metronidazole reductively in the treatment of trichomoniasis. It is the first hydrogenosomal ferredoxin to have its structure determined. The structure of TvFd reveals a monomeric, 93 residue protein with a fold similar to that of other known [2Fe-2S] ferredoxins. It contains nine hydrogen bonds to the sulfur atoms of the cluster, which is more than the number predicted on the basis of the spectroscopic data. The TvFd structure contains a large dipole moment like adrenodoxin, and appears to have a similar interaction domain. Our analysis demonstrates that TvFd has a unique cavity near the iron-sulfur cluster that exposes one of the inorganic sulfur atoms of the cluster to solvent. This cavity is not seen in any other [2Fe-2S] ferredoxin with known structure, and is hypothesized to be responsible for the high rate of metronidazole reduction by TvFd.

Peptides Constrained to Type VI beta-Turns. 1. Evidence for an Exceptionally Stable Intramolecular Hydrogen Bond.

The synthesis and conformational analysis of conjugates of amino acids with a type VI beta-turn dipeptide mimic (1) is described. The mimic possessed high structural similarity to the central two residues of the turn and was constrained from rotation about two of the four single bonds. Coupling of amino acids to the carboxyl group of the mimic afforded conjugates that were capable of forming intramolecular hydrogen bonds. In nonpolar solvents, IR and NMR spectra of the conjugates indicated that the amide hydrogen of the amino acid residue was hydrogen bonded to the carbonyl group of the N-terminal carbamate functionality, as in typical beta-turns. In the hydrogen-bonding solvent DMSO, the intramolecular hydrogen bond was still present, according to the temperature dependence of the chemical shift. The presence of the i, i + 3 hydrogen bond in the conjugates of mimic 1 was substantiated by the spectral properties of conjugates of the isomeric mimic 3, which showed no evidence for the presence of an intramolecular hydrogen bond. The results from these studies suggest that the intramolecularly hydrogen-bonded type VIa turn is an inherently more stable conformation for a peptide than the non-hydrogen-bonded type VIb conformation, in the absence of other structural constraints.

Peptides Constrained to Type VI beta-Turns. 2. Antiparallel beta-Ladder Formation.

The preparation and characterization of an extensive series of bis-amino acid conjugates of a novel beta-turn mimic are described. The conjugates were prepared by coupling amino acid residues to the amino and carboxyl groups of the mimic, which represented the central two residues of a peptide constrained to the type VI turn conformation. The resultant adducts had the capability to form either singly or doubly hydrogen-bonded conformations, which represented beta-turn or antiparallel beta-ladder structures, respectively. In the majority of the bis-amino acid conjugates of the cis-lactam 1 (or its enantiomer), only the interior hydrogen bond, characteristic of the singly hydrogen-bonded conformation, was present, according to NMR and IR spectra. When the lactam 1 or its enantiomer were coupled to L-Phe at its carboxyl group and N-AcGly at its amino group, the spectral properties indicated the presence of the doubly hydrogen-bonded form. The results are consistent with other workers' studies that demonstrated that aryl residues following Pro stabilize antiparallel type VI turn structures and that the propensity of an amino acid to adopt a beta-conformation in proteins is highly dependent on context.

Novel Bicyclic Lactams as XaaPro Type VI beta Turn Mimics: Design, Synthesis, and Evaluation.

The design, enantioselective synthesis, and structural characterization of novel bicyclic lactams as peptide mimics of the type VI beta turn is described. The mimics duplicate the conformation of the backbone and disposition of the side-chain atoms of the central two residues of the turn. The Gly L-Pro mimic, lactam 6, was prepared in good overall yield starting from (S)-2-(2'-propenyl)proline. (1)H NMR spectroscopy defined the relative stereochemistry of the substituents and conformational characteristics of the six-membered ring of the lactam; X-ray crystallographic analysis confirmed the conformational and stereochemical assignment. Examination of the crystal structure of lactam 6 revealed that the central amide bond was twisted appreciably out of planarity. The twisting of the amide bond was attributed to angle strain resulting from the presence of the sp(2)-hybridized nitrogen atom at the junction of the two rings. Alkylation of the enolate of the N,N-dimethylformamidine derivative of lactam 6 with benzyl bromide afforded stereoselectively the formamidine 11, a mimic of an L-Phe L-Pro dipeptide in the type VI turn conformation. The efficient synthetic route to highly functionalized peptidomimetics such as 11 will prove highly useful in peptide structure-function studies.