Biology subjects

jelinek, r.

Publications and source records attributed to jelinek, r..

2 recordsLinked to original sources

bioRxiv2023

Staphylococcus aureus functional amyloids catalyze degradation of β-lactam antibiotics

Antibiotic resistance of bacteria is considered one of the most alarming developments in modern medicine. While varied pathways for bacteria acquiring antibiotic resistance have been identified, there still are open questions concerning the mechanisms underlying resistance. Here, we show that alpha phenol-soluble modulins (PSMs), functional bacterial amyloids secreted by Staphylococcus aureus, catalyze breakup of {beta}-lactams, a prominent class of antibiotic compounds. Specifically, we show that PSM2 and, particularly, PSM3 catalyze hydrolysis of the amide-bond four-member ring of nitrocefin, a widely used {beta}-lactam surrogate. Microscopic and spectroscopic analyses of several PSM3 variants and correlation with their catalytic activities allowed mapping of the catalytic sites on the amyloid fibrils surface, specifically underscoring the key roles of the cross- fibril organization, and the combined electrostatic and nucleophilic functions of the lysine residue array. This study unveils a previously unknown role of functional bacterial amyloids as catalytic agents for antibiotic compounds, pointing to possible mechanisms for antibiotic resistance of bacteria. ToC Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/526669v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@184141org.highwire.dtl.DTLVardef@643e8forg.highwire.dtl.DTLVardef@147488borg.highwire.dtl.DTLVardef@ebb7fa_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2021

Tryptophol acetate and tyrosol acetate, metabolites secreted by a probiotic yeast, halt cytokine storm

Probiotic fermented foods are perceived as contributing to human health, however solid evidence for their presumptive therapeutic systemic benefits is generally lacking. Here we report that tryptophol acetate and tyrosol acetate, small molecule metabolites secreted by the probiotic milk-fermented yeast Kluyveromyces marxianus inhibit hyperinflammation (e.g., "cytokine storm"). Comprehensive in vivo and in vitro analyses, employing LPS-induced hyperinflammation models, reveal dramatic effects of the molecules, added in tandem, on mice morbidity, laboratory parameters, and mortality. Specifically, we observed attenuated levels of the pro-inflammatory cytokines IL-6, IL-1, IL-1{beta} and TNF-, and reduced reactive oxygen species. Importantly, tryptophol acetate and tyrosol acetate did not completely suppress pro-inflammatory cytokine generation, rather brought their concentrations back to baseline levels thus maintaining core immune functions, including phagocytosis. The anti-inflammatory effects of tryptophol acetate and tyrosol acetate were mediated through downregulation of TLR4, IL-1R, and TNFR signaling pathways and increased A20 expression, leading to NF-kB inhibition. Overall, this work illuminates phenomenological and molecular details underscoring anti-inflammatory properties of small molecules identified in a probiotic mixture, pointing to potential therapeutic avenues against severe inflammation.

immunology↗