Succinylation modification provides a new sight in the treatment of immunocompromised populations with drug-resistant Aspergillus fumigatus infection

ABSTRACT: The invasive infection of Aspergillus fumigatus poses a serious threat to human health worldwide, especially in immunocompromised patients. At present, triazole drugs are the most common antifungal drugs for aspergillosis. However, due to the emergence of drug-resistant strains, the effect of triazole drugs is greatly limited, resulting in the death rate of infection can even be as high as 80%. Succinylation modification, as a new post-translational modification, is receiving more and more attention but its biological function in triazole resistance is still unclear. In this study, we creatively initiated a first screening of lysine succinylation in A.fumigatus. We identified and found that some of the succinylation sites were significantly different among strains with unequal itraconazole (ITR) resistance. Bioinformatics analysis indicated that the succinylated proteins were involved in a wide range of cellular functions with diverse subcellular localizations and cell metabolism is the most prominent. Further antifungal sensitivity test confirmed the synergistic fungicidal effect of dessuccinylase inhibitor nicotinamide (NAM) on ITR resistant A.fumigatus. In vivo experiment, the treatment of NAM alone or combined with ITR both significantly increased the survival of neutropenia mice with A.fumigatus infection. In vitro experiment showed that NAM enhanced the killing effect of Thp-1 macrophages on A.fumigatus conidia. Our results suggest that lysine succinylation may play an indispensable role in the ITR-resistance of A.fumigatus. Dessuccinylase inhibitor NAM alone or combined with ITR exerted a good effect against A.fumigatus infection, which was concerned with its synergistic fungicidal effect as well as enhancing macrophage killing effect. These results provide mechanistic insights for the treatment of ITR-resistant fungi infection.

ORGANISM(S): Aspergillus Fumigatus

SUBMITTER: Xiaochun Xue  

PROVIDER: PXD040137 | iProX | Wed Feb 15 00:00:00 GMT 2023

REPOSITORIES: iProX