Coenzyme A metabolism in fungi: a new frontier in antifungal therapy

SUMMARYFungal infections are the leading cause of mortality among eukaryotic pathogens. They are responsible for approximately 150 million cases of severe illness and 3.8 million deaths annually. This global health threat is exacerbated by the limited arsenal of clinically approved antifungal drugs, particularly for the treatment of life-threatening invasive infections. The rise of multidrug-resistant fungal strains further underscores the urgent need for new classes of antifungals with novel mechanisms of action. In this context, the fungal coenzyme A (CoA) biosynthesis pathway has emerged as a promising therapeutic target due to its essential role in fungal physiology and key differences from its human counterpart. This review explores the critical role of CoA biosynthesis in fungal metabolism and highlights recent advances in the discovery and characterization of novel compounds targeting this pathway. Some of these emerging candidates act both as standalone inhibitors and as broad-spectrum potentiators of existing antifungals through their ability to enhance strain susceptibility and counteract mechanisms of drug detoxification and multidrug resistance. Collectively, these findings establish CoA metabolism as a compelling target for the next generation of antifungal therapies, offering a multipronged strategy to overcome the limitations of current treatment options and reduce fungal-related mortality.