Dereplication of Natural Product Antifungals via Liquid Chromatography-Tandem Mass Spectrometry and Chemical Genomics.

Recently expanded reports of multidrug-resistant fungal infections underscore the need to develop new and more efficient methods for antifungal drug discovery. A ubiquitous problem in natural product drug discovery campaigns is the rediscovery of known compounds or their relatives; accordingly, we have integrated Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for structural dereplication and Yeast Chemical Genomics for bioprocess evaluation into a screening platform to identify such compounds early in the screening process. We identified 450 fractions inhibiting and the resistant strains of and among more than 40,000 natural product fractions.

Genetic interaction analysis of transcription factors and in the regulation of respiration and fluconazole susceptibility.

is the second most common cause of invasive candidiasis and is widely known to have reduced susceptibility to fluconazole relative to many other spp. Upc2A is a transcription factor that regulates ergosterol biosynthesis gene expression under conditions of sterol stress such as azole drug treatment or hypoxia. Through an microevolution experiment, we found that loss-of-function mutants of the ATF/CREB transcription factor suppresses the fluconazole hyper-susceptibility of the ∆ mutant.

The distinctive pharmacokinetic profile of rezafungin, a long-acting echinocandin developed in the era of modern pharmacometrics.

Echinocandin drugs are the current first-line therapy for fungal infections caused by Candida spp. Most patients require once-daily intravenous (IV) administration in a hospital or outpatient setting for treatment, which may negatively impact their quality of life and stress healthcare resources. Similar to other echinocandins, the novel FDA-, EMA-, and Medical and Healthcare Products Regulatory Agency-approved echinocandin, rezafungin (CD101), exhibited strong antifungal activity against several fungal pathogens and a low drug-drug interaction liability, which are important for medically complex patients.

pharmacodynamic evaluation of the novel nystatin derivative BSG005 in the invasive candidiasis and invasive pulmonary aspergillosis mouse models.

Nystatin, a polyene, is one of the oldest antifungal drugs with wide potency. BSG005 is a novel, chemically modified, nystatin-like molecule in development for systemic therapy. We evaluated the pharmacokinetic/pharmacodynamic (PK/PD) relationships and target exposures using invasive pulmonary aspergillosis (IPA) and invasive candidiasis (IC) infection models for BSG005 against common fungal pathogens including , , , and .