Dataset Information

Itaconate ameliorates methicillin-resistant Staphylococcus aureus-induced acute lung injury through the Nrf2/ARE pathway.

ABSTRACT:

Background

Methicillin-resistant Staphylococcus aureus (MRSA) are a critical predisposing factor of sepsis in the clinic. As a product of human energy metabolism and immune response, itaconate can effectively reduce inflammation in the body. This research employed 4-octyl itaconate (4-OI) to illustrate that itaconate exerted anti-inflammatory effects to protect the body from acute lung injury (ALI) induced by MRSA.

Methods

HE staining and immunohistochemistry are used to evaluate the MRSA-induced ALI in mice. WB and qPCR were used to verify the effect of 4-OI on inflammation and oxidative stress caused by MRSA. Molecular docking was used to verify the binding sites of 4-OI and Keap1.

Results

We demonstrated that 4-OI treatment increased the survival ratio, attenuated the pathological damage, inhibited neutrophil infiltration, and reduced lung bacterial burden in the mouse MRSA pneumonia model. 4-OI decreased the expression of inflammatory factors by stimulating the Nrf2 in vivo and in vitro. Furthermore, 4-OI exerted its effect by promoting nuclear transport of Nrf2 in vitro. The results of molecular docking indicated that 4-OI bound to the pocket of Keap1 and exerted a stable interaction. Both Nrf2 inhibitors (ML385) and Nrf2^-/- mice abolished the protective effect of 4-OI on MRSA-induced inflammation both in vitro and in vivo.

Conclusions

4-OI prevents lung damage caused by MRSA bacteremia via activating Nrf2/ARE pathway.

SUBMITTER: Liu G

PROVIDER: S-EPMC8106008 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Methicillin resistant Staphylococcus aureus (MRSA) infection is becoming refractory to existing antibiotic therapy owing to the inherent ability of S. aureus to develop rapid resistance and is considered a major threat to public health. We found that a natural isolate of Bacillus pumilus from the Columbia River Estuary produces a strong anti-MRSA compound, amicoumacin A. As amicoumacin A has been reported to exhibit anti-microbial, anti-inflammatory, and anti-ulcer activities, we sought to uncover its mechanism of action. Genome-wide transcriptome analysis of S. aureus COL in response to amicoumacin A showed alteration in the expression of genes involved in several cellular processes including cell envelope turnover, cross-membrane transport, virulence, metabolism, and general stress response. The most highly induced gene was lrgA, encoding an antiholin-like product, which has been shown to be induced in response to a collapse of membrane potential. In order to gain further insight into the mechanism of action of amicoumacin A, a whole genome comparison of wild-type COL and amicoumacin A-resistant mutants isolated by serial passage method was carried out. Single point mutations resulting in codon substitutions were uncovered in several distinct genes: ksgA, RNA dimethyltranferase; fusA, elongation factor G; dnaG, primase, ; lacD, tagatose 1,6-bisphosphate aldolase, ; and SACOL0611, encoding a putative glycosyl transferase gene. Based on these results, a candidate approach was undertaken to recreate the same amino acid substitution individually in FusA and KsgA, each of which resulted in two-fold resistance towards amicoumacin A. The fusA gene is known as the site for fusidic acid- resistant mutations; however the codon substitutions in EF-G that cause amicoumacin A resistance and fusidic acid resistance occur in separate domains and do not bring about cross resistance. Taken together, these results suggest that amicoumacin A might cause perturbation of the cell membrane and lead to energy dissipation. Decreased rates of cellular metabolism including protein synthesis and DNA replication in resistant strains might allow cells to compensate for membrane dysfunction and thus increase cell survivability.