Synthesis of the Hydroxamate Siderophore Nα-Methylcoprogen B in Scedosporium apiospermum Is Mediated by sidD Ortholog and Is Required for Virulence.

Scedosporium species rank second among the filamentous fungi capable to colonize chronically the respiratory tract of patients with cystic fibrosis (CF). Nevertheless, there is little information on the mechanisms underpinning their virulence. Iron acquisition is critical for the growth and pathogenesis of many bacterial and fungal genera that chronically inhabit the CF lungs. In a previous study, we showed the presence in the genome of Scedosporium apiospermum of several genes relevant for iron uptake, notably SAPIO_CDS2806, an ortholog of sidD, which drives the synthesis of the extracellular hydroxamate-type siderophore fusarinine C (FsC) and its derivative triacetylfusarinine C (TAFC) in Aspergillus fumigatus. Here, we demonstrate that Scedosporium apiospermum sidD gene is required for production of an excreted siderophore, namely, Nα-methylcoprogen B, which also belongs to the hydroxamate family. Blockage of the synthesis of Nα-methylcoprogen B by disruption of the sidD gene resulted in the lack of fungal growth under iron limiting conditions. Still, growth of ΔsidD mutants could be restored by supplementation of the culture medium with a culture filtrate from the parent strain, but not from the mutants. Furthermore, the use of xenosiderophores as the sole source of iron revealed that S. apiospermum can acquire the iron using the hydroxamate siderophores ferrichrome or ferrioxamine, i.e., independently of Nα-methylcoprogen B production. Conversely, Nα-methylcoprogen B is mandatory for iron acquisition from pyoverdine, a mixed catecholate-hydroxamate siderophore. Finally, the deletion of sidD resulted in the loss of virulence in a murine model of scedosporiosis. Our findings demonstrate that S. apiospermum sidD gene drives the synthesis of a unique extracellular, hydroxamate-type iron chelator, which is essential for fungal growth and virulence. This compound scavenges iron from pyoverdine, which might explain why S. apiospermum and Pseudomonas aeruginosa are rarely found simultaneously in the CF lungs.

Recent trends in the epidemiology, diagnosis, treatment, and mechanisms of resistance in clinical Aspergillus species: A general review with a special focus on the Middle Eastern and North African region.

Globally, more than billion people suffer from fungal infections each year. The early diagnosis of aspergillosis is mandatory for successful treatment outcome. As careful testing takes time, epidemiological surveillance is crucial to guide individual patient therapy and to promote a high standard of health care. In this paper, we first present current trends in the epidemiology and antifungal susceptibility patterns of Aspergillus spp. in Middle Eastern and North African (MENA) countries in order to support infectious disease specialists and health workforces in this geographic area to treat adequately patients with aspergillosis. Then we discuss the existing literature data regarding the available diagnostic tools and antifungal resistance mechanisms of Aspergillus spp. Although a limited number of studies were reviewed here, the currently available data show that Aspergillus infections are not negligible in the MENA region, and that the emergence of antifungal resistance is a growing health issue, especially among immunocompromised patients.

Antileishmanial and antifungal activities of xanthanolides isolated from Xanthium macrocarpum.

Seven xanthanolides, xanthinosin, xanthatin, 4-hydroxyxanthinosin, xanthinin, 4-epiisoxanthanol, 4-epixanthanol, 2-hydroxyxanthinosin and 4-oxobedfordia acid, were isolated from the fruits of Xanthium macrocarpum. A valuation of the antifungal activity of these xanthanolides against Candida albicans, Candida glabrata and Aspergillus fumigatus and of their antileishmanial activity against Leishmania infantum and Leishmania mexicana is presented.

Synthesis of reduced xanthatin derivatives and in vitro evaluation of their antifungal activity.

Abstract The synthesis of new xanthanolide derivatives is reported starting from xanthatin, a sesquiterpenic lactone isolated from Xanthium macrocarpum (Asteraceae). In vitro evaluation of their antifungal activity has been investigated.

Investigation of the antifungal activity of caledonixanthone E and other xanthones against Aspergillus fumigatus.

Among the different xanthones previously isolated from the stem bark of Calophyllum caledonicum, caledonixanthone E presented the strongest activity (MIC (80) = 8 microg/mL) in acidic conditions (pH 3) against the human pathogenic fungus Aspergillus fumigatus. Phase-contrast microscopy studies suggested the assembly or synthesis of cell wall components as the target of the drug. Moreover, the use of fluorescent lectins further supported an impact of caledonixanthone E on the synthesis of chitin, the major structural polysaccharide of the fungal wall. These results suggest that caledonixanthone E may be an interesting model for the design of new antifungal drugs.

Colony morphology switching of Candida lusitaniae and acquisition of multidrug resistance during treatment of a renal infection in a newborn: case report and review of the literature.

Candida lusitaniae is an emerging opportunistic pathogen which exhibits an unusual antifungal susceptibility pattern. We describe a case of fatal renal infection due to C. lusitaniae in a very low birth weight neonate who was treated with short courses of fluconazole given alternately with amphotericin B. A colony morphology switching was detected on the standard primary culture medium by changes in colony size. Switching was shown to affect deeply the susceptibility to amphotericin B. Afterwards, the switched phenotype developed a cross resistance to fluconazole and itraconazole. Several issues raised by this case are discussed in the light of an extensive review of the literature. Our observations point out the importance of both the detection of colony morphology switching and the close monitoring of antifungal susceptibility in the management of infections due to C. lusitaniae. A judicious therapeutic strategy should prevent the acquisition of multidrug resistance during antifungal therapy.

Relationships between respiration and susceptibility to azole antifungals in Candida glabrata.

Over the past two decades, the incidence of infections due to Candida glabrata, a yeast with intrinsic low susceptibility to azole antifungals, has increased markedly. Respiratory deficiency due to mutations in mitochondrial DNA (mtDNA) associated with resistance to azoles frequently occurs in vitro in this species. In order to specify the relationships between respiration and azole susceptibility, the effects of respiratory chain inhibitors on a wild-type isolate of C. glabrata were evaluated. Respiration of blastoconidia was immediately blocked after extemporaneous addition of potassium cyanide, whereas a 4-h preincubation was required for sodium azide. Antifungal susceptibility determined by a disk diffusion method on Casitone agar containing sodium azide showed a significant decrease in the susceptibility to azoles. Biweekly subculturing on Casitone agar supplemented with sodium azide was therefore performed. This resulted after 40 passages in the isolation of a respiration-deficient mutant, as suggested by its lack of growth on glycerol-containing agar. This respiratory deficiency was confirmed by flow cytometric analysis of blastoconidia stained with rhodamine 123 and by oxygraphy. Moreover, transmission electron microscopy and restriction endonuclease analysis of the mtDNA of mutant cells demonstrated the mitochondrial origin of the respiratory deficiency. Finally, this mutant exhibited cross-resistance to all the azoles tested. In conclusion, blockage of respiration in C. glabrata induces decreased susceptibility to azoles, culminating in azole resistance due to the deletion of mtDNA. This mechanism could explain the induction of petite mutations by azole antifungals which have been demonstrated to act directly on the mitochondrial respiratory chain.

New and antifungal xanthones from Calophyllum caledonicum.

Two new xanthones, namely caledonixanthones E (1) and F (2), were isolated from the stem bark of Calophyllum caledonicum (Guttiferae). The structural elucidation of these compounds was mainly established on the basis of 1D, 2D NMR and HRMS spectroscopic analysis. Among the isolated compounds, eight other known xanthones were also identified in the course of this phytochemical study. In addition to this report, a preliminary evaluation of the antifungal properties of these polyphenolic compounds against Aspergillus fumigatus and Candida albicans is presented.