26 - Copper-only Superoxide Dismutases as Novel Drug Targets for Fungal Pathogens

Abstract

Superoxide dismutases (SODs) are metalloenzymes that disproportionate superoxide produced by aerobic metabolism as well as the oxidative bursts present at the host-pathogen interface. Bimetallic eukaryotic Cu/Zn SOD molecules are potent antioxidants found in most intracellular compartments and in extracellular locations. Our lab has recently discovered a new class of extracellular copper-only SODs found only in the fungal kingdom that are structurally distinct from bimetallic Cu/Zn SODs while still retaining equivalent catalytic efficiency. This novel class of copper only SODs are unique in that they lack zinc-binding residues and an electrostatic loop, creating an open active site that is accessible to solvent. Importantly these copper only SODs have been shown to be virulence factors in fungal pathogens such as Candida albicans and Histoplasma capsulatum. The uniquely accessible active site of these copper only SODs and their role in pathogenesis make them good candidates for selective drug design. We screened for compounds that selectively inhibit copper-only C. albicans SOD5 over mammalian Cu/Zn SOD1. We found that pyrithione zinc (PZ), a well-known antifungal in dandruff shampoo, has highly selective and potent activity against C. albicans copper only SOD5. The metal complex of pyrithione (Zn or Cu) appears to be more effective against SOD5 than pyrithione alone, suggesting the di-pyrithione structure selectively targets the open active site of fungal Cu-only SODs. Metal-pyrithione complexes are promising candiates for new anti-fungals that target the curious family of fungal Cu-only SODs.