Inhibition of Siderophores in Blocking Fungal Infection

The growing problem of antimicrobial resistance is gaining large momentum owing to its deadly consequences. The reduced efficacy and ineffectiveness of known antifungals resulted to search for novel drug targets in fungal metabolism. Out of several approaches adopted to curb fungal pathogenesis, one of the most important strategies is to diminish the iron requirement to fungal pathogen by blocking the siderophore-mediated iron transport. The iron uptake mechanism is regulated by transporter proteins, and this process is responsible for maintaining survival and virulence of microorganism. Chemically, siderophores are chelating agents and have strong metal ion-binding property. They are produced almost by all the pathogenic microbes by utilizing L-ornithine for their production via siderophore biosynthetic pathway. Targeting the biosynthetic pathway of siderophore formation, their utilization, and subsequent uptake by pathogen proves to be an effective alternative approach to develop host-friendly antifungal drug targets. Further, the detailed exploration of enzymes involved in production of siderophore could lead to development of inhibitors acting either as structural mimics of siderophore or carrying entirely different structural framework. Trojan horse approach (THA) further enhances the application of siderophore by utilizing siderophore-drug conjugate (SDC) concept for delivering antibiotics (ciprofloxacin, ampicillin, amoxicillin, etc.) to the tolerant pathogen, thus improving the efficacy and sensitivity of known drugs.