Pseudallenes A and B, new sulfur-containing ovalicin sesquiterpenoid derivatives with antimicrobial activity from the deep-sea cold seep sediment-derived fungus Pseudallescheria boydii CS-793.

Pseudallenes A and B (1 and 2), the new and rare examples of sulfur-containing ovalicin derivatives, along with three known analogues 3-5, were isolated and identified from the culture extract of Pseudallescheria boydii CS-793, a fungus obtained from the deep-sea cold seep sediments. Their structures were established by detailed interpretation of NMR spectroscopic and mass spectrometric data. X-ray crystallographic analysis confirmed and established the structures and absolute configurations of compounds 1-3, thus providing the first characterized crystal structure of an ovalicin-type sesquiterpenoid. In the antimicrobial assays, compounds 1-3 showed broad-spectrum inhibitory activities against several plant pathogens with MIC values ranging from 2 to 16 µg/mL.

Antiparasitic Ovalicin Derivatives from Pseudallescheria boydii, a Mutualistic Fungus of French Guiana Termites.

Social insects are in mutualism with microorganisms, contributing to their resistance against infectious diseases. The fungus Pseudallescheria boydii SNB-CN85 isolated from termites produces ovalicin derivatives resulting from the esterification of the less hindered site of the ovalicin epoxide by long-chain fatty acids. Their structures were elucidated using spectroscopic analysis and semisynthesis from ovalicin. For ovalicin, these compounds displayed antiprotozoal activities against Plasmodium falciparum and Trypanosoma brucei, with IC50 values of 19.8 and 1.1 µM, respectively, for the most active compound, i.e., ovalicin linoleate. In parallel, metabolomic profiling of a collection of P. boydii strains associated with termites made it possible to highlight this class of compounds together with tyroscherin derivatives in all strains. Finally, the complete genome of P. boydii strains was obtained by sequencing, and the cluster of potential ovalicin and ovalicin biosynthesis genes was annotated. Through these metabolomic and genomic analyses, a new ovalicin derivative named boyden C, in which the 6-membered ring of ovalicin was opened by oxidative cleavage, was isolated and structurally characterized.

In Vivo Efficacy of Olorofim against Systemic Scedosporiosis and Lomentosporiosis.

Clinically relevant members of the Scedosporium/Pseudallescheria species complex and Lomentospora prolificans are generally resistant against currently available systemic antifungal agents in vitro, and infection due to these species is difficult to treat. We studied the in vivo efficacy of a new fungicidal agent, olorofim (formerly F901318), against scedosporiosis and lomentosporiosis in neutropenic animals. Cyclophosphamide-immunosuppressed CD-1 mice infected by Scedosporium apiospermum, Pseudallescheria boydii (Scedosporium boydii), and Lomentospora prolificans were treated by intraperitoneal administration of olorofim (15 mg/kg of body weight every 8 h for 9 days). The efficacy of olorofim treatment was assessed by the survival rate at 10 days postinfection, levels of serum (1-3)-ß-d-glucan (BG), histopathology, and fungal burdens of kidneys 3 days postinfection. Olorofim therapy significantly improved survival compared to that of the untreated controls; 80%, 100%, and 100% of treated mice survived infection by Scedosporium apiospermum, Pseudallescheria boydii, and Lomentospora prolificans, respectively, while less than 20% of the control mice (phosphate-buffered saline [PBS] treated) survived at 10 days postinfection. In the olorofim-treated neutropenic CD-1 mice infected with any of the three species, serum BG levels were significantly suppressed and fungal DNA detected in the target organs was significantly lower than in controls. Furthermore, histopathology of kidneys revealed no or only a few lesions with hyphal elements in the olorofim-treated mice, while numerous fungal hyphae were present in control mice. These results indicate olorofim to be a promising therapeutic agent for systemic scedosporiosis/lomentosporiosis, devastating emerging fungal infections that are difficult to treat with currently available antifungals.

Orbital abscess caused by Exophiala dermatitidis following posterior subtenon injection of triamcinolone acetonide: a case report and a review of literature related to Exophiala eye infections.

BACKGROUND: Subtenon injection of triamcinolone acetonide (STTA) has been widely adopted in the clinical setting of ophthalmology and its infectious complications are rare. However, orbital abscess following STTA has been reported in seven cases. Furthermore, although eye infections due to Exophiala species are uncommon, there have been 19 cases to date. E. jeanselmei, E. phaeomuriformis, E. werneckii, and E. dermatitidis have been reported to cause human eye infections; however, to the best of our knowledge, orbital abscess caused by E. dermatitidis has not yet been reported. We describe the first documented case of fungal orbital abscess caused by E. dermatitidis following STTA. We also review the related literature of orbital abscess following STTA, as well as eye infections caused by the four Exophiala species. CASE PRESENTATION: The patient was a 69-year-old Japanese woman with diabetic mellitus. She had a macular oedema in her right eye, which occurred secondary to branch retinal vein occlusion. An orbital abscess caused by E. dermatitidis occurred 4 months after the second STTA for the macular oedema, which was successfully treated by a surgical debridement and systemic administration of voriconazole. CONCLUSIONS: Our findings in the patient and from our literature survey caution ophthalmologists to the fact that STTA can cause fungal orbital infections, especially in diabetic patients. Furthermore, surgical treatment is one of the most important risk factors.

Exploration of Indole Alkaloids from Marine Fungus Pseudallescheria boydii F44-1 Using an Amino Acid-Directed Strategy.

The composition of the culture medium has great influence on the metabolite production of the marine fungus Pseudallescheria boydii F44-1. By adding amino acids to GPY culture medium, two new bisindole alkaloids, pseudboindoles A and B (1 and 2), together with 11 known indole alkaloids were isolated from the culture broth. Their structures were elucidated by comprehensive analysis of the NMR, MS, IR, and UV spectra. The 3,3'-cyclohexylidenebis(1H-indole) (3) showed cytotoxic activity against various cancer cell lines.

Orbital apex syndrome secondary to a fungal nasal septal abscess caused by Scedosporium apiospermum in a patient with uncontrolled diabetes: a case report.

BACKGROUND: Orbital apex syndrome is a localized type of orbital cellulitis, where mass lesions occur at the apex of the cranial nerves. Although nasal septal abscess is uncommon, the organism most likely to cause nasal septal abscess is Staphylococcus aureus, and fungal septal abscesses are rare. Here we present an extremely rare and serious case of orbital apex syndrome secondary to fungal nasal septal abscess caused by Scedosporium apiospermum in a patient with uncontrolled diabetes. CASE PRESENTATION: A 59-year-old man with a 1-month history of headache underwent consultation in an otolaryngological clinic of a general hospital. He was diagnosed with nasal septal abscess and was treated with incisional drainage and 1 month of an antibiotic drip; however, his symptoms persisted. The patient later complained of diplopia due to bilateral abducens nerve palsy, and was then referred to the department of Otolaryngology - Head and Neck Surgery, Kobe City Medical Center General Hospital. The septal lesion was biopsied under general anesthesia, and S. apiospermum was detected using polymerase chain reaction. The patient was treated with an antifungal drug and surgical resection of the lesion was performed. Although the patient survived, he lost his eyesight. CONCLUSIONS: This patient represents the second reported case of nasal septal abscess and orbital apex syndrome caused by S. apiospermum. If not treated properly, septal abscess can be life-threatening and cause severe complications, such as ablepsia.

Pseudallescheria boydii with Aspergillus fumigatus and Aspergillus terreus in a Critically Ill Hematopoietic Stem Cell Recipient with ARDS.

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

Scedosporium apiospermum: An unreported cause of fungal sporotrichoid-like lymphocutaneous infection in Australia and review of the literature.

Scedosporium apiospermum is a fungus emerging as a rare but important cause of both localised and disseminated infections in immunocompromised patients. Most cutaneous lesions present as mycetoma, however a review of the literature revealed an increasing number of cases worldwide presenting with lymphocutaneous spread resembling sporotrichosis. An 85-year-old man with an extensive medical history including type II diabetes mellitus and meningioma presented with crusted haemorrhagic areas on the dorsum of his left foot and multiple crusted nodules extending proximally along his leg in a sporotrichoid-like lymphocutaneous pattern. A mycological examination and culture of the cutaneous tissue found the fungus, Scedosporium apiospermum.

A novel antibacterial tyroscherin derivative with a natural unprecedented morpholine-2, 3-dione structural unit from the fungus Pseudallescheria boydii.

A novel tyroscherin derivative named pseudallecin A (1) with a natural unprecedented morpholine-2, 3-dione structural unit, and a new biogenic synthesis related organic acid named pseudallecin B (2) were purified from a symbiotic fungus Pseudallescheria boydii derived from Pomacea canaliculata. Their structures were elucidated via spectroscopic analyses and ECD calculation. Pseudallecin A exhibited strong inhibitory activities against both Gram-positive Escherichia coli and Gram-negative Staphylococcus aureus.

Fungal keratitis caused by Pseudallescheria boydii: clinical and mycological characteristics.

BACKGROUND: Pseudallescheria keratitis is rare but important type of fungal keratitis because of the inherently resistance of the organism to many existing antifungal agents. METHODS: Slit-lamp and confocal microscopy were used for clinical examinations. Fungal isolates were identified based on morphological characteristics and DNA sequence of the internal transcribed spacer region (ITS). In vitro antifungal susceptibility testing for fungal isolates was performed according to the Clinical and Laboratory Standards Institute (CLSI, M38-A2). RESULT: All patients had a history of ocular trauma. In clinical examination hypopion were seen in three patients. The main antifungal medications were topical voriconazole. After treatment the visual acuity of all patients improved in 2-3 weeks. CONCLUSION: All four patients of Pseudallescheria keratitis had similar clinical features. Accurate and rapid identification of species should be helpful in treating p. boydii keratitis.

Biodegradation of Tetrahydrofuran by the Newly Isolated Filamentous Fungus Pseudallescheria boydii ZM01.

Tetrahydrofuran (THF) is widely used as a precursor for polymer syntheses and a versatile solvent in industries. THF is an environmental hazard and carcinogenic to humans. In the present study, a new THF-degrading filamentous fungus, Pseudallescheria boydii ZM01, was isolated and characterized. Strain ZM01 can tolerate a maximum THF concentration of 260 mM and can completely degrade 5 mM THF in 48 h, with a maximum THF degradation rate of 133.40 mg THF h-1 g-1 dry weight. Growth inhibition was not observed when the initial THF concentration was below 150 mM, and the maximum THF degradation rate was still maintained at 118.21 mg THF h-1 g-1 dry weight at 50 mM THF, indicating the great potential of this strain to degrade THF at high concentrations. The initial key metabolic intermediate 2-hydroxytetrahydrofuran was detected and identified by gas chromatography (GC) analyses for the first time during the THF degradation process. Analyses of the effects of initial pH, incubation temperature, and heavy metal ions on THF degradation revealed that strain ZM01 can degrade THF under a relatively wide range of conditions and has good degradation ability under low pH and Cu2+ stress, suggesting its adaptability and applicability for industrial wastewater treatment.

Fungal keratitis caused by rare organisms.

PURPOSE: To report two rare cases of filamentous fungal keratitis. METHODS: Two non-consecutive patients presented with suspicious fungal keratitis. After performing the smear and culture, medical therapy was started for them. They underwent slit photography and in vivo confocal microscopy (IVCM) in their follow-up visits. RESULTS: The patients were 33-year-old and 56-year-old farmer men. They both mentioned a history of ocular trauma by plants. During their follow-up visits, corneal infiltration density and fungal hyphae density decreased in slit-lamp biomicroscopy and IVCM, respectively. The corresponding organisms were Pseudallescheria boydii (P. boydii) and Colletotrichum coccodes. CONCLUSIONS: It is important to be aware of these rare organisms and their antibiotic susceptibility. There was not any specific confocal feature for the presented fungal keratitis that was different from other filamentous fungal hyphae; however, confocal scan is a good choice to follow the response to the treatment.

Pulmonary Scedosporium apiospermum Infection with Pulmonary Tumorlet in an Immunocompetent Patient.

Scedosporium apiospermum is an opportunistic fungus that can cause various types of infections, including localized infections and life-threatening disseminated infections, particularly in immunocompromised patients. Treatment is especially challenging due to its multidrug resistance. We herein report the case of a 73-year-old woman who was non-immunocompromised but developed S. apiospermum lung infection and a pulmonary tumorlet. To our knowledge, this is the first report of the coexistence of pulmonary S. apiospermum infection and tumorlet. The lung lesion was successfully treated by surgical excision without any antifungal agents, and no recurrence of the tumorlet or S. apiospermum infection has occurred.

Scedosporium apiospermum: An Emerging Fatal Cause of Fungal Abscess and Ventriculitis after Near-drowning.

Herein, we describe a fatal case of central nervous system (CNS) pseudallescheriasis following near-drowning. A 13-year-old boy, who had been successfully resuscitated after near-drowning, presented with a transient episode of mental confusion during a hospital stay after recovering from severe aspiration pneumonia and respiratory failure. A magnetic resonance imaging (MRI) scan of the brain showed a small brain abscess in the left basal ganglia and ventriculitis in the left lateral ventricle. The brain abscess and ventriculitis did not respond to 4 weeks of antibiotic treatment and appeared even worse on a follow-up MRI. A diagnosis of CNS pseudallescheriasis was only possible with invasive stereotactic biopsy and aspiration of the abscess that showed the presence of hyphae and Scedosporium apiospermum. CNS pseudallescheriasis did not respond to multiple combinations of antifungal agents, including amphotericin B, isoconazole, itraconazole, and voriconazole. Two ventricular drainages and insertion of Ommaya reservoirs with intraventricular injection of voriconazole were insufficient to halt the infection. The patient passed away from sudden septic shock 2 months after identification of the brain abscess and ventriculitis. The patient's diagnosis was delayed because multiple examinations of the cerebrospinal fluid did not show positive cultures and could only be obtained from the aspirates of stereotactic biopsy. Physicians should be aware of CNS pseudallescheriasis associated with near-drowning because of the difficulty of diagnosis and the high mortality rate (70%) owing to poor responses to currently available antifungal agents.

Scedosporium apiosermum infection of the "Native" valve: Fungal endocarditis in an orthotopic heart transplant recipient.

Scedosporium apiospermum is an increasingly appreciated pathogen in immunosuppressed patients. We present a case of S. apiospermum endocarditis in a 70-year-old male who had undergone orthotopic heart transplant. Echocardiogram demonstrated a 1.4 cm tricuspid valve vegetation. He underwent valve replacement, complicated by fatal massive post-operative haemorrhage. Valve cultures grew S. apiospermum. To our knowledge, our case is the first reported instance of endocarditis caused by S. apiospermum in a recipient of a cardiac transplant.

Evaluation of the matrix-assisted laser desorption/ionization time-of-flight mass spectrometry Bruker Biotyper for identification of Penicillium marneffei, Paecilomyces species, Fusarium solani, Rhizopus species, and Pseudallescheria boydii.

We evaluated the performance of matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), the MALDI Bruker Biotyper system (microflex LT; Bruker Daltonik GmbH, Bremen, Germany), on the identification of 50 isolates of clinically encountered molds, including Penicillium marneffei (n = 28), Paecilomyces species (n = 12), Fusarium solani (n = 6), Rhizopus species (n = 3), and Pseudallescheria boydii (n = 1). The isolates were identified to species levels by sequence analysis of the internal transcribed spacer (ITS) regions using primers ITS1 and ITS4. None of the 28 genetically well characterized isolates of P. marneffei were identified as P. marneffei by MALDI-TOF MS, because P. marneffei was not present in either Bruker general library (DB 5627) or Bruker filamentous fungi library V1.0. However, the rate of accurate identification as P. marneffei (score value ≥ 2.000) was 85.7% based on newly created database from one P. marneffei strain (NTUH-3370) by MALDI Biotyper system. Sequencing analysis of these 22 non-P. marneffei isolates of molds revealed seven Paecilomyces variotii, six F. solani, four Paecilomyces lilacinus, and one each of Paecilomyces sinensis, Rhizopus arrhizus, R. oryzae, R. microspores, and P. boydii. Although all the seven P. variotii isolates, four of the six F. solani, two of the four P. lilacinus, and two of the three isolates of Rhizopus species, and the P. boydii isolate had concordant identification results between MALDI-TOF MS and sequencing analysis, the score values of these isolates were all of <1.700. This study indicated that the MALDI Bruker Biotyper is ineffective for identifying P. marneffei and other unusual molds because of the current database limitations. Therefore, it is necessary to continuously update the MALDI-TOF MS databases.

The epidemiology of pseudallescheriasis complicating transplantation: Nosocomial and community-acquired infection.

The epidemiology of two cases of pseudallescheriasis in organ transplant patients are described and the disease in that population is reviewed. Disseminated hospital-acquired infection occurred in a liver transplant recipient and was fatal despite therapy with miconazole. A heart transplant recipient developed localized disease following soil contamination of soft tissue trauma which was cured with surgical resection and miconazole therapy. Itraconazole showed in vitro activity against Pseudallescheria boydii and should be evaluated in pseudallescheriasis. P. boydii infections are important complications of transplantation and should be considered in the differential diagnosis of community-acquired as well as nosocomial fungal infections in this population.