Alexidine dihydrochloride has broad spectrum a ctivities against diverse fungal pathogens

Abstract

word count: 175 28 Manuscript word count: 4267 29 2Abstract. 30 Invasive fungal infections due to Candida albicans, Aspergillus fumigatus and 31 Cryptococcus neoformans, constitute a substantial threat to hospitalized, 32 immunocompromised patients. Further, the presence of drug-recalcitrant biofilms on 33 medical devices, and emergence of drug-resistant fungi such as Candida auris, 34 introduce treatment challenges with current antifungal drugs. Worse, currently there is 35 no approved drug capable of obviating preformed biofilms which increases the chance 36 of infection relapses. Here, we screened a small molecule Prestwick Chemical Library, 37 consisting of 1200 FDA approved off-patent drugs, against C. albicans, C. auris and A. 38 fumigatus, to identify those that inhibit growth of all three pathogens. Inhibitors were 39 further prioritized for their potency against other fungal pathogens, and their ability to kill 40 preformed biofilms. Our studies identified the bis-biguanide Alexidine dihydrochloride 41 (AXD), as a drug with the highest antifungal and anti-biofilm activity against a diverse 42 range of fungal pathogens. Finally, AXD significantly potentiated the efficacy of 43 fluconazole against biofilms, displayed low mammalian cell toxicity, and eradicated 44 biofilms growing in mice central venous catheters in vivo, highlighting its potential as a 45 pan-antifungal drug. 46Importance. 47The prevalence of fungal infections has seen a rise in the past decades due to 48 advances in modern medicine leading to an expanding population of device-associated 49 and immunocompromised patients. Furthermore, the spectrum of pathogenic fungi has 50 changed, with the emergence of multi-drug resistant strains such as C. auris. High 51 mortality related to fungal infections point to major limitations of current antifungal 52 3 therapy, and an unmet need for new antifungal drugs. We screened a library of 53 repurposed FDA approved inhibitors to identify compounds with activities against a 54 diverse range of fungi, in varied phases of growth. The assays identified Alexidine 55 dihydrochloride (AXD) to have pronounced antifungal activity including against 56 preformed biofilms, at concentrations lower than mammalian cell toxicity. AXD 57 potentiated the activity of fluconazole and amphotericin B against Candida biofilms in 58 vitro, and prevented biofilm growth in vivo. Thus AXD has the potential to be developed 59 as a pan-antifungal, anti-biofilm drug. 61Introduction. 62Fungal pathogens responsible for invasive fungal infections (IFIs) are a leading cause of 63 human mortality, killing approximately one and a half million people every year, despite 64 treatment with antifungal drugs (1). Of concern, the current incidence of fungal-related 65 deaths is reported to be even higher than mortality due to tuberculosis or malaria (2). A 66 vast majority of IFIs result from species belonging to Cryptococcus, Candida or 67 Aspergillus (3). However, fungi such as molds other than Aspergillus, and non-albicans...

Antibodies targeting Candida albicans Als3 and Hyr1 antigens protect neonatal mice from candidiasis

“…Fluconazole resistant C. albicans strain CA6 was received from the Fungus Testing Laboratory at the University of Texas Health Science Center at San Antonio. The MIC 50 of fluconazole against this strain is 16 (50). Routinely, the organisms were cultured overnight in yeast peptone dextrose (YPD) broth (Difco) at 30°C with shaking prior to use for in vitro and in vivo assays.…”

Broad sensitivity ofCandida aurisstrains to quinolones and mechanisms of resistance

“…These types of screens have identified a number of promising compounds, including ebselen, miltefosine, and alexidine dihydrochloride. Three of these published screens were conducted with the same library (the Prestwick Chemical Library with 1,280 compounds), but the hits from these screens were not always concordant (49 different compounds were identified in these screens: 3 in all three, 18 in two, and 28 in only one) (44)(45)(46)(47)(48)(49).…”