Integration of Transcriptomics and Proteomics to Elucidate Inhibitory Effect and Mechanism of Antifungalmycin B from Marine Streptomyces hiroshimensis in Treating Talaromyces marneffei

<i>Talaromyces marneffei</i> (TM) is an opportunistic pathogenic fungus that mainly infects immunocompromised patients. Currently, the global prevalence of talaromycosis caused by TM is increasing, leading to an increased demand for anti-TM drugs. In our previous study, a novel 28-membered macrolide compound, antifungalmycin B (ANB), was isolated from <i>Streptomyces hiroshimensis</i> GXIMD 06359, exhibiting significant antifungal properties. However, its in vivo mechanisms and direct antifungal effects warrant further investigation. In this study, we employed a mouse model in conjunction with transcriptomic and proteomic approaches to explore the antifungal activity of ANB against <i>T. marneffei</i>. In an in vivo mouse model infected with <i>T. marneffei</i> infection, ANB significantly reduced fungal burdens in the liver, spleen, lungs, and kidneys. Additionally, it markedly decreased the levels of reactive oxygen species (ROS) and cytokines, including interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. Proteomic and transcriptomic studies, complemented by parallel reaction monitoring (PRM) analysis, revealed that ANB effectively disrupted acid biosynthesis and cellular energy metabolism, thereby impairing mitochondrial functions in <i>T. marneffei</i>. These effects were exerted through multiple pathways. These findings highlight the potential of ANB as a versatile inhibitor of polyene macrolide-resistant fungi, offering a promising therapeutic avenue for the treatment of talaromycosis.