Enhanced fungal specificity and in vivo therapeutic efficacy of a C-22-modified FK520 analog against C. neoformans.

IMPORTANCE: Fungal infections cause significant morbidity and mortality globally. The therapeutic armamentarium against these infections is limited, and the development of antifungal drugs has been hindered by the evolutionary conservation between fungi and the human host. With rising resistance to the current antifungal arsenal and an increasing at-risk population, there is an urgent need for the development of new antifungal compounds. The FK520 analogs described in this study display potent antifungal activity as a novel class of antifungals centered on modifying an existing orally active FDA-approved therapy. This research advances the development of much-needed newer antifungal treatment options with novel mechanisms of action.

Calcineurin in fungal virulence and drug resistance: Prospects for harnessing targeted inhibition of calcineurin for an antifungal therapeutic approach.

Increases in the incidence and mortality due to the major invasive fungal infections such as aspergillosis, candidiasis and cryptococcosis caused by the species of Aspergillus, Candida and Cryptococcus, are a growing threat to the immunosuppressed patient population. In addition to the limited armamentarium of the current classes of antifungal agents available (pyrimidine analogs, polyenes, azoles, and echinocandins), their toxicity, efficacy and the emergence of resistance are major bottlenecks limiting successful patient outcomes. Although these drugs target distinct fungal pathways, there is an urgent need to develop new antifungals that are more efficacious, fungal-specific, with reduced or no toxicity and simultaneously do not induce resistance. Here we review several lines of evidence which indicate that the calcineurin signaling pathway, a target of the immunosuppressive drugs FK506 and cyclosporine A, orchestrates growth, virulence and drug resistance in a variety of fungal pathogens and can be exploited for novel antifungal drug development.

Reconstructing genome evolution in historic samples of the Irish potato famine pathogen.

Responsible for the Irish potato famine of 1845-49, the oomycete pathogen Phytophthora infestans caused persistent, devastating outbreaks of potato late blight across Europe in the 19th century. Despite continued interest in the history and spread of the pathogen, the genome of the famine-era strain remains entirely unknown. Here we characterize temporal genomic changes in introduced P. infestans. We shotgun sequence five 19th-century European strains from archival herbarium samples--including the oldest known European specimen, collected in 1845 from the first reported source of introduction. We then compare their genomes to those of extant isolates. We report multiple distinct genotypes in historical Europe and a suite of infection-related genes different from modern strains. At virulence-related loci, several now-ubiquitous genotypes were absent from the historical gene pool. At least one of these genotypes encodes a virulent phenotype in modern strains, which helps explain the 20th century's episodic replacements of European P. infestans lineages.