A cost-effective strategy for artificial siderophores with potential biological applications using a fragment-based approach for targeted antimicrobial therapy Simnikiwe Nogqala 1 , Rui Krause 1 , Xavier Siwe-Noundou 2 1 Department of Chemistry, Rhodes University, South Africa, 2 Pharmaceutical Sciences Department, School of Pharmacy, Sefako Makgatho Health Sciences University, South Africa In the intricate tapestry of life on Earth, iron stands as a foundational element, essential for countless biological processes. However, the dance of iron in the natural world is a delicate one, fraught with scarcity and strict regulation. Enter siderophores, remarkable molecules produced by an array of microorganisms, and a beacon of hope for the pursuit of good health. Siderophores , often affectionately referred to as "iron scavengers," are versatile compounds with an astonishing affinity for binding iron. Their structural diversity is a testament to nature's ingenuity, a finely tuned response to the challenge of acquiring this vital nutrient in iron-deprived environments. Beyond their ecological significance, siderophores have unveiled a new frontier in the quest for good health. Their potential applications span a spectrum of medical marvels, offering solutions to the most pressing challenges of our time. In a world where antimicrobial resistance looms, siderophores emerge as powerful allies. These molecules can be harnessed to disrupt the crucial process of iron acquisition in bacterial pathogens, rendering them vulnerable to our existing antibiotics. The result? Enhanced antibacterial therapies that safeguard our health. Fungi, too, seek iron for their growth and survival. Siderophores, with their capacity to intercept this vital resource, open new frontiers in antifungal treatments. By targeting fungal iron acquisition mechanisms, we unveil promising strategies to combat fungal infections and promote good health. Iron overload disorders and certain cancers can threaten good health by causing iron imbalances in the body. Siderophores can be repurposed as iron chelators, expertly binding excess iron and offering a lifeline to those seeking equilibrium in their quest for good health. The world of vaccines benefits from the prowess of siderophores too. These molecules, with their ability to engage both the immune system and microbial iron metabolism, hold promise as vaccine adjuvants. They can enhance our body's immune responses, fortifying our defenses and bolstering good health. Siderophores are not merely passive observers in the battle against antibiotic resistance; they are key strategists. By intercepting bacterial iron acquisition pathways, they render resistant bacteria more susceptible to existing treatments, rekindling hope for good health in the face of this global crisis. But the story doesn't end here. In this study, we embark on a new chapter, one that blends nature's elegance with human ingenuity. We propose a groundbreaking synthetic strategy to produce siderophores and employ them in a trojan-horse approach to tackle antimicrobial resistance head-on. These synthesized siderophores will be ingeniously conjugated with antibiotics, creating siderophore-antibiotic conjugates that can penetrate the bacterial cell wall with unprecedented precision. The implications are profound, this will help restore and preserve good health. References 1. Skwarecki et al., 2020. Synthetic strategies in construction of organic low molecular-weight carrier-drug conjugates. Bioorganic chemistry, 104, p104311. 2. Lui et al. 2022, Recent advances in siderophore biology of Shewanella. Frontiers in Microbiology, 13, p823758.
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