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Identification of the malonylation modification in staphylococcus aureus and insight into the regulators in biofilm Formation.

ABSTRACT: Post-translational modifications (PTMs) are critical regulators of bacterial biofilm formation, but the role of lysine malonylation (Kmal) in biofilm formation is still poorly understood. In this study, we analyzed the dynamic changes of protein malonylation of Staphylococcus aureus (S. aureus) DC15 during biofilm formation based on antibody affinity enrichment combined with quantitative proteomics. Quantitative profiling identified 2,833 malonylated sites across 788 proteins, with significant enrichment in biofilm-associated proteins. Twelve conserved motifs, including Kmal******R and Kmal****R (* represents any amino acid residue), dominated the malonyl proteome landscape in S. aureus. The combined analysis of modified and quantitative proteomics revealed the quorum-sensing system as a key regulatory hub in S. aureus biofilm formation. In particular, the response regulator, AgrA, showed decreased expression but increased malonylation at the K2, K11 and K216 sites during S. aureus biofilm formation, suggesting functional compensation. Structural and phylogenetic analysis showed that the key malonylation sites (K216) of protein AgrA were evolutionarily conserved in Gram-positive pathogens including Bacillus cereus. Molecular docking analysis found that antimicrobial peptide BCp12 and natural compound chlorogenic acid could bind with the malonylation sites in AgrA (ΔG = 6.888 and 5.302 kcal/mol, respectively). This study provides a new perspective for understanding the general rules of bacterial biofilm formation and developing broad-spectrum anti-biofilm drugs.

ORGANISM(S): Staphylococcus Aureus

SUBMITTER: Yanan Shi

PROVIDER: PXD066374 | iProX | Mon Jul 21 00:00:00 BST 2025

REPOSITORIES: iProX

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Identification of the malonylation modification in staphylococcus aureus and insight into the regulators in biofilm Formation

Project description:Post-translational modifications (PTMs) are critical regulators of bacterial biofilm formation, but the role of lysine malonylation (Kmal) in biofilm formation is still poorly understood. In this study, we analyzed the dynamic changes of protein malonylation of Staphylococcus aureus (S. aureus) DC15 during biofilm formation based on antibody affinity enrichment combined with quantitative proteomics. Quantitative profiling identified 2,833 malonylated sites across 788 proteins, with significant enrichment in biofilm-associated proteins. Twelve conserved motifs, including Kmal******R and Kmal****R (* represents any amino acid residue), dominated the malonyl proteome landscape in S. aureus. The combined analysis of modified and quantitative proteomics revealed the quorum-sensing system as a key regulatory hub in S. aureus biofilm formation. In particular, the response regulator, AgrA, showed decreased expression but increased malonylation at the K2, K11 and K216 sites during S. aureus biofilm formation, suggesting functional compensation. Structural and phylogenetic analysis showed that the key malonylation sites (K216) of protein AgrA were evolutionarily conserved in Gram-positive pathogens including Bacillus cereus. Molecular docking analysis found that antimicrobial peptide BCp12 and natural compound chlorogenic acid could bind with the malonylation sites in AgrA (ΔG = 6.888 and 5.302 kcal/mol, respectively). This study provides a new perspective for understanding the general rules of bacterial biofilm formation and developing broad-spectrum anti-biofilm drugs.

2025-07-21 | PXD066349 |

GdpS contributes to Staphylococcus aureus biofilm formation by regulation of eDNA release

Project description:In Staphylococcus aureus, the role of the GGDEF domain containing protein GdpS remains poorly understood. Previous studies reported that gdpS mutant strains had decreased biofilm formation due to changes in icaADBC expression that were independent of cyclic-di-GMP levels. We deleted gdpS in three unrelated S. aureus isolates, and analyzed the resultant mutants for alterations in biofilm formation, metabolism and transcription. Dynamic imaging during biofilm development showed that GdpS inhibited early biofilm formation in only two out of the three strains examined, without affecting bacterial survival. However, quantification of biofilm formation using crystal violet staining revealed that inactivation of gdpS affected biofilm formation in all three studied strains. Extraction of metabolites from S. aureus cells confirmed the absence of cyclic-di-GMP, suggesting that biofilm formation in this species differs from that in other Gram-positive organisms. In addition, targeted mutagenesis demonstrated that the GGDEF domain was not required for GdpS activity. Transcriptomic analysis revealed that the vast majority of GGDEF-regulated genes were involved in virulence, metabolism, cell wall biogenesis and eDNA release. Finally, expression of lrgAB or deletion of cidABC in a strain lacking gdpS confirmed the role of GdpS on regulation of eDNA production that occurred without an increase in cell autolysis. In summary, S. aureus GdpS contributes to cell-to-cell interactions during early biofilm formation by influencing expression of lrgAB and cidABC mediated eDNA release. We conclude that GdpS acts as a negative regulator of eDNA release. Three strains UAMS-1, SA113 and SA564 were used in this study to compare wt with gdpS mutant after 5 hours of growth in static conditions (biofilm formation).

2014-06-30 | E-GEOD-48656 | biostudies-arrayexpress

GdpS contributes to Staphylococcus aureus biofilm formation by regulation of eDNA release

2014-06-30 | GSE48656 | GEO

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Repurposing cinacalcet suppresses multi-drug resistant Staphylococcus aureus by disruption of cell membrane and inhibits biofilm by targeting IcaR

Project description:Multi-drug resistant Staphylococcus aureus (S. aureus) infections continously threaten public health. The rapid escalation in morbidity and mortality rates associated with methicillin-resistant S. aureus (MRSA) infections necessitates the urgent development of novel antimicrobial agents. Our study reveals that the FDA-approved drug cinacalcet (CNA) effectively functions as an antibacterial and anti-biofilm agent against S. aureus without detectable resistance. It evidently improved survival rate of mice infected with clinical multi-resistant S. aureus in a pneumonia model. Subsequent proteomic and biochemical experiments suggest that the primary antibacterial mechanism involves membrane structure disruption, ATP content reduction, and reactive oxygen species (ROS) production. Concurrently, LiP-SMap combined with biochemical validation indicates that CNA inhibits biofilm formation by targeting IcaR, a negative regulator of icaADBC, thereby enhancing its binding capacity to the ica operator DNA and subsequently suppressing extracellular polysaccharide formation. Importantly, compared to vancomycin, CNA demonstrates stronger biofilm bacterial clearance in a mouse thigh infection model. Collectively, our findings propose that CNA can be repurposed as a potential therapeutic agent for treating multidrug-resistant S. aureus infections and their associated biofilms.

2024-02-07 | PXD041266 | Pride

Inhibition of Staphylococcus aureus biofilm formation by gurmarin, a plant-derived cyclic peptide

Project description:Staphylococcus aureus is an opportunistic pathogen capable of causing various infections ranging from superficial skin infections to life-threatening severe diseases, including pneumonia and sepsis. This bacterium is attached to biotic and abiotic surfaces and forms biofilms that are resistant to conventional antimicrobial agents and clearance by host defenses. Infections associated with biofilms may result in longer hospitalizations, a need for surgery, and may even result in death. Agents that inhibit the formation of biofilms and virulence without affecting bacterial growth to avoid the development of drug resistance could be useful for therapeutic purposes. In this regard, we identified and isolated a small cyclic peptide, gurmarin, from a plant source that inhibited the formation of S. aureus biofilm without affecting the growth rate of the bacterium. We determined the gene expression of S. aureus biofilm treated with gurmarin and compared it to the untreated control biofilms. Differentially expressed genes were identified and their roles in the inhibition of S. aureus biofilms by gurmarin were analyzed.

2022-09-21 | E-MTAB-12154 | biostudies-arrayexpress

Effect of Hamamelitannin, vancomycin and combination treatment of Hamamelitannin and vancomycin on gene expression in S. aureus Mu50 biofilms

Project description:Novel anti-infective agents targeting Staphylococcus aureus and capable of increasing S. aureus susceptibility towards antibiotics are needed. One alternative approach is targeting the bacterial quorum sensing (QS) system. QS is a process by which bacteria produce and detect signal molecules and thereby coordinate their behaviour, virulence and biofilm formation in a cell-density-dependent manner. Hamamelitannin (HAM) was previously suggested to target the S. aureus QS system, thereby increasing the susceptibility of S. aureus biofilms towards vancomycin. However, mechanistic insights are still lacking. For this reason, we evaluated the effect of Hamamelitannin, vancomycin and combination treatment of Hamamelitannin and vancomycin on gene expression in S. aureus Mu50 biofilms.

2017-08-25 | E-MTAB-3816 | biostudies-arrayexpress

A dual inhibitor of Staphylococcus aureus virulence and biofilm attenuates expression of major toxins and adhesins

Project description:Staphylococcus aureus is a major bacterial pathogen that invades and damages host tissue by the expression of devastating toxins. We here performed a phenotypic screen of 35 molecules that were structurally inspired by previous hydroxyamide-based S. aureus virulence inhibitors compiled from commercial sources or designed and synthesized de novo. One of the most potent compounds, AV73, did not only reduce hemolytic alpha-hemolysin expression in S. aureus but also impeded in vitro biofilm formation. The effect of AV73 on bacterial proteomes and extracellular protein levels were analyzed by quantitative proteomics and revealed a significant down-regulation of major virulence and biofilm promoting proteins. To elucidate the mode of action of AV73, target identification was performed using affinity-based protein profiling (AfBPP).

2018-03-05 | PXD008067 | Pride

SaeRS-dependent inhibition of biofilm formation in Staphylococcus aureus Newman

Project description:The SaeRS two-component regulatory system of Staphylococcus aureus is known to affect the expression of many genes. The SaeS protein is the histidine kinase responsible for phosphorylation of the response regulator SaeR. In S. aureus Newman, the sae system is constitutively expressed due to a point mutation in saeS, relative to other S. aureus strains, which results in substitution of proline for leucine at amino acid 18. Strain Newman is unable to form a robust biofilm and we report here that the biofilm-deficient phenotype is due to the saeSP allele. Replacement of the Newman saeSP with saeSL, or deletion of saeRS, resulted in a biofilm-proficient phenotype. Newman culture supernatants were observed to inhibit biofilm formation by other S. aureus strains, but did not affect biofilm formation by S. epidermidis. Culture supernatants of Newman saeSL or Newman ΔsaeRS had no significant effect on biofilm formation. The inhibitory factor was inactivated by incubation with proteinase K, but survived heating, indicating that the inhibitory protein is heat-stable. The inhibitory protein was found to affect the attachment step in biofilm formation, but had no effect on preformed biofilms. Replacement of saeSL with saeSP in the biofilm-proficient S. aureus USA300 FPR3757 resulted in the loss of biofilm formation. Culture supernatants of USA300 FPR3757 saeSP, did not inhibit biofilm formation by other staphylococci, suggesting that the inhibitory factor is produced but not secreted in the mutant strain. A number of biochemical methods were utilized to isolate the inhibitory protein. Although a number of candidate proteins were identified, none were found to be the actual inhibitor. In an effort to reduce the number of potential inhibitory genes, RNA-Seq analyses were done with wild-type strain Newman and the saeSL and ΔsaeRS mutants. RNA-Seq results indicated that sae regulates many genes that may affect biofilm formation by Newman.

2015-04-30 | GSE65827 | GEO

Granulocytic myeloid-derived suppressor cell activity during biofilm infection is regulated by a glycolysis-HIF-1α axis (scRNA-Seq)

Project description:Staphylococcus aureus is a leading cause of biofilm-associated prosthetic joint infection (PJI). A primary contributor to infection chronicity is an expansion of granulocytic myeloid-derived suppressor cells (G-MDSCs) that are critical for orchestrating the anti-inflammatory biofilm milieu. Single-cell sequencing and bioinformatic metabolic algorithms were used to explore the link between G-MDSC metabolism and S. aureus PJI outcome. Glycolysis and the hypoxic response through hypoxia-inducible factor-1 alpha (HIF-1α) were significantly enriched in G-MDSCs. Interfering with both pathways in vivo, using a 2-deoxyglucose nanopreparation and granulocyte-targeted HIF-1α conditional knockout mice, respectively, attenuated G-MDSC-mediated immunosuppression and reduced bacterial burden in a mouse model of S. aureus PJI. In addition, scRNA-seq analysis of granulocytes from PJI patients also showed an enrichment in glycolysis and hypoxic response genes. These findings support the importance of a glycolysis/HIF-1α axis in promoting G-MDSC anti-inflammatory activity and biofilm persistence during PJI.

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