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Candida auris is an emerging multidrug-resistant fungal pathogen. With high mortality rates, there is an urgent need for new antifungals to combat C. auris . Possible antifungal targets include Cu-only superoxide dismutases (SODs), extracellular SODs that are unique to fungi and effectively combat the superoxide burst of host immunity. Cu-only SODs are essential for the virulence of diverse fungal pathogens; however, little is understood about these enzymes in C. auris . We show here that C. auris secretes an enzymatically active Cu-only SOD ( Caur SOD4) when cells are starved for Fe, a condition mimicking host environments. Although predicted to attach to cell walls, Caur SOD4 is detected as a soluble extracellular enzyme and can act at a distance to remove superoxide. Caur SOD4 selectively binds Cu and not Zn, and Cu binding is labile compared to bimetallic Cu/Zn SODs. Moreover, Caur SOD4 is susceptible to inhibition by various metal-binding drugs that are without effect on mammalian Cu/Zn SODs. Our studies highlight Caur SOD4 as a potential antifungal target worthy of consideration.

Kinase inhibitors comprise a diverse cohort of chemical scaffolds that are active in multiple biological systems. Currently, thousands of eukaryotic kinase inhibitors are commercially available, have well-characterized targets, and often carry pharmaceutically favorable toxicity profiles. Recently, our group disclosed that derivatives of the natural product meridianin D, a known inhibitor of eukaryotic kinases, modulated behaviors of both Gram-positive and Gram-negative bacteria. Herein, we expand our exploration of kinase inhibitors in Gram-negative bacilli utilizing three commercially available kinase inhibitor libraries and, ultimately, identify two chemical structures that potentiate colistin (polymyxin E) in multiple strains. We report IMD-0354, an inhibitor of IKK-β, as a markedly effective adjuvant in colistin-resistant bacteria and also describe AR-12 (OSU-03012), an inhibitor of pyruvate dehydrogenase kinase-1 (PDK-1), as a potentiator in colistin-sensitive strains. This report comprises the first description of the novel cross-reactivity of these molecules.

In 2016, the World Health Organization deemed antibiotic resistance one of the biggest threats to global health, food security, and development. The need for new methods to combat infections caused by antibiotic resistant pathogens will require a variety of approaches to identifying effective new therapeutic strategies. One approach is the identification of small molecule adjuvants that potentiate the activity of antibiotics of demonstrated utility, whose efficacy is abated by resistance, both acquired and intrinsic. To this end, we have identified compounds that enhance the efficacy of antibiotics normally ineffective against Gram-negative pathogens because of the outer membrane permeability barrier. We identified two adjuvant compounds that dramatically enhance sensitivity of Acinetobacter baumannii to macrolide and glycopeptide antibiotics, with reductions in minimum inhibitory concentrations as high as 256-fold, and we observed activity across a variety of clinical isolates. Mode of action studies indicate that these adjuvants likely work by modulating lipopolysaccharide synthesis or assembly. The adjuvants were active in vivo in a Galleria mellonella infection model, indicating potential for use in mammalian infections.