Scientists have unveiled mandimycin—a newly discovered antibiotic with unparalleled properties that may revolutionize multidrug-resistant (MDR) fungal infection treatment—according to a study in Nature. Unlike conventional antibiotics, mandimycin boasts a unique mode of action: targeting fungal cell membrane phospholipids, disrupting ion balance, and sidestepping resistance mechanisms. Its potent, broad-spectrum fungicidal effects mark a significant leap in combating hard-to-treat fungal infections, offering hope in the battle against resilient superbugs.
s from an ambitious analysis by researchers from China Pharmaceutical University and Shandong University of over 316,000 bacterial genomes, pinpointing biosynthetic gene clusters (BGCs) encoding mycosamine-rich polyene macrolides. Mandimycin’s structure is a marvel of nature: a 38-membered macrolactone ring adorned with three unique sugars, including a rare dideoxysaccharide. This intricate composition gives mandimycin extraordinary solubility—9,700 times higher than the gold-standard antifungal amphotericin B—overcoming longstanding challenges of poor bioavailability in antifungal agents.
In laboratory tests, mandimycin exhibited potent, broad-spectrum efficacy against deadly MDR fungal pathogens, including Candida, Cryptococcus, and Aspergillus species, identified as critical threats by the World Health Organization. Remarkably, its minimum inhibitory concentrations (MICs) ranged from just 0.125 to 2 μg/mL, demonstrating robust fungicidal activity. Unlike existing polyene antifungals that target ergosterol in fungal cell membranes, mandimycin operates through a novel mechanism. It binds specifically to essential phospholipids, such as phosphatidylinositol, disrupting membrane integrity and inducing cell collapse. This unique mode of action circumvents cross-resistance to existing antifungals, a frequent hurdle in combating MDR strains.
A safer, more effective antifungal
The antibiotic’s resistance profile is equally impressive. Despite rigorous attempts, researchers could not generate resistant fungal mutants—a rarity in antifungal research. Structural studies revealed that mandimycin’s antifungal potency relies heavily on its dideoxysaccharide moiety, underscoring its importance in phospholipid binding. Compared to amphotericin B, mandimycin demonstrated dramatically lower nephrotoxicity and no hemolytic effects, even at high concentrations. Testing in human renal and other cell lines revealed 7–22 times weaker toxicity for mandimycin, and in vivo mouse studies showed minimal kidney injury markers at doses as high as 30 mg/kg.
Mandimycin also exhibited exceptional antifungal efficacy against MDR Candida albicans, achieving a 100% survival rate in mice at 10 mg/kg and significantly reducing fungal burdens in major organs. The drug proved potent across various delivery methods, including subcutaneous, intravenous, and oral administration. With favorable pharmacokinetics and no observable side effects, mandimycin outperformed amphotericin B in both safety and effectiveness, marking a critical step forward in combating MDR fungal infections.
Mandimycin represents a new frontier in antifungal therapy, blending potent efficacy with innovative action. With its potential to address rising fungal infections in immunocompromised patients and overcome antifungal resistance, mandimycin could transform global healthcare landscapes. This discovery not only highlights the unexplored potential of microbial biodiversity but also offers hope against the escalating threat of antifungal resistance.
Website: International Conference on Infectious Diseases
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