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Triptolide clears Staphylococcus aureus infection by targeting XIAP to induce host apoptosis while preserving gut microbiota homeostasis [iBDMDs]

ABSTRACT: Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the efficacy of conventional antibiotics. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With the multi-targeting and immunomodulatory properties, Traditional Chinese Medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored. Here, we identified triptolide as a compound that facilitates intracellular clearance of SA and MRSA. Mechanistic studies revealed that triptolide directly binds to the X‑linked inhibitor of apoptosis protein (XIAP) to inhibit XIAP-caspase interaction, thereby releasing caspase inhibition and inducing apoptosis. Moreover, treatment with triptolide reduced bacterial loads and alleviated lung inflammation in mice infected with SA and MRSA, concurrently maintaining microbiota homeostasis and improving metabolic function. Taken together, these findings establish triptolide as a promising lead compound for the development of HDT against SA and MRSA infections.

INSTRUMENT(S):

ORGANISM(S): Staphylococcus Aureus Mus Musculus (mouse)

TISSUE(S): Cell Culture, Macrophage

SUBMITTER: Zhe Lu

LAB HEAD: liu cuihua lab

PROVIDER: PXD074476 | Pride | 2026-05-18

REPOSITORIES: Pride

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			Action	DRS
	HF01_20250724_50wins_ZLQ_LL_SA_3604_protein_1.raw	Raw
	HF01_20250724_50wins_ZLQ_LL_SA_3604_protein_2.raw	Raw
	HF01_20250724_50wins_ZLQ_LL_SA_3604_protein_3.raw	Raw
	HF01_20250724_50wins_ZLQ_LL_SA_DMSO_protein_1.raw	Raw
	HF01_20250724_50wins_ZLQ_LL_SA_DMSO_protein_2.raw	Raw

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Project description:Background: Staphylococcus aureus (SA) remains a global health threat due to its increasing drug resistance and intracellular persistence, which compromise the efficacy of conventional antibiotics. Host-directed therapy (HDT) has emerged as a promising alternative by modulating host immunity. With the multi-targeting and immunomodulatory properties, Traditional Chinese Medicine (TCM) monomers represent ideal candidates for HDT. However, their ability to promote host immunity-mediated SA clearance remains largely unexplored.Purpose: To identify the critical TCM monomer that facilitates the clearance of intracellular SA and methicillin-resistant SA (MRSA), as well as to elucidate its mechanism.Methods: Fifty-five TCM monomers potentially regulating host immunity were screened to identify a compound promoting intracellular SA/MRSA clearance. The mechanism was investigated using transcriptomics, proteomics, molecular dynamics simulations, and biochemical assays. In vivo holistic regulation was examined in infected mice through lung pathology and multi-omics analysis (transcriptomics, proteomics, metagenomics, and metabolomics).Results: Triptolide was identified as a potent facilitator of host immunity-mediated intracellular clearance of SA and MRSA, without exerting direct bactericidal effects. Mechanistically, triptolide directly binds to the X-linked inhibitor of apoptosis protein (XIAP), disrupting its interaction with caspases to relieve their inhibition and thereby induce apoptosis. Furthermore, in murine infection models, triptolide treatment reduced bacterial loads and alleviated lung inflammation, while concurrently preserving microbiota homeostasis and improving metabolic function.Conclusion: This study establishes a proof of concept for triptolide as a HDT candidate against SA and MRSA infections, with a mechanism that not only enhances host apoptosis-mediated pathogen clearance but also preserves host microbiota and metabolic homeostasis.

Project description:This is the standard model described in the article: Systems analysis of effector caspase activation and its control by X-linked inhibitor of apoptosis protein. Rehm M, Huber HJ, Dussmann H, Prehn JH. EMBO J. 2006 Sep 20;25(18):4338-49. Epub 2006 Aug 24. PMID:16932741, doi:10.1038/sj.emboj.7601295; Abstract: Activation of effector caspases is a final step during apoptosis. Single-cell imaging studies have demonstrated that this process may occur as a rapid, all-or-none response, triggering a complete substrate cleavage within 15 min. Based on biochemical data from HeLa cells, we have developed a computational model of apoptosome-dependent caspase activation that was sufficient to remodel the rapid kinetics of effector caspase activation observed in vivo. Sensitivity analyses predicted a critical role for caspase-3-dependent feedback signalling and the X-linked-inhibitor-of-apoptosis-protein (XIAP), but a less prominent role for the XIAP antagonist Smac. Single-cell experiments employing a caspase fluorescence resonance energy transfer substrate verified these model predictions qualitatively and quantitatively. XIAP was predicted to control this all-or-none response, with concentrations as high as 0.15 microM enabling, but concentrations >0.30 microM significantly blocking substrate cleavage. Overexpression of XIAP within these threshold concentrations produced cells showing slow effector caspase activation and submaximal substrate cleavage. Our study supports the hypothesis that high levels of XIAP control caspase activation and substrate cleavage, and may promote apoptosis resistance and sublethal caspase activation in vivo. This model is slightly altered from the description in the article. Cytochrome C and SMAC release from the mitochondrion is modelled as simple first order kinetics, giving the same form as the (integrated) equations in the supplement of the article. The apoptosome formation is modelled equally - and independent of the Cytochrome C release. The speed is either limited by the Apaf1 or ProCaspase9 concentration, whichever is higher, symbolised via the parameter with the ID apolim. Also, once the substrate concentration falls below 1 percent, the event Production_Breakdown is triggered, leading to a breakdown of XIAP and procaspase3 production and turning off of the enhanced/proteosomal degradation (degradation rate for reactions 38,39,40,43,44,46,48,50,51 changes from 0.0347 to 0.0058). Originally created by libAntimony v1.3 (using libSBML 3.4.1) This model originates from BioModels Database: A Database of Annotated Published Models (http://www.ebi.ac.uk/biomodels/). It is copyright (c) 2005-2012 The BioModels.net Team. For more information see the terms of use. To cite BioModels Database, please use: Li C, Donizelli M, Rodriguez N, Dharuri H, Endler L, Chelliah V, Li L, He E, Henry A, Stefan MI, Snoep JL, Hucka M, Le Novère N, Laibe C (2010) BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. BMC Syst Biol., 4:92.

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Triptolide clears Staphylococcus aureus infection by targeting XIAP to induce host apoptosis while preserving gut microbiota homeostasis [iBDMDs]

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