Interplay of CodY and CcpA in Regulating Central Metabolism and Biofilm Formation in Staphylococcus aureus

Bulock, Logan L.; Ahn, Jongsam; Shinde, Dhananjay; Pandey, Sanjit; Sarmiento, Cleofes; Thomas, Vinai Chittezham; Guda, Chittibabu; Bayles, Kenneth W.; Sadykov, Marat R.

doi:10.1128/jb.00617-21

Cited by 10 publications

(13 citation statements)

References 54 publications

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“…In addition to ccpA , down-regulated codY (another global transcription factor) could also decrease the levels of guanosine triphosphate and isoleucine in MRSA (figs. S24 and S26) ( 64 ). It is reported that codY and ccpA jointly sense the nutritional and control carbon and nitrogen fluxes by controlling catabolism and anabolism involved in sugar and amino acid utilization ( 63 , 64 ).…”

Section: Resultsmentioning

confidence: 99%

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms

Zhang

Chen

et al. 2023

Sci. Adv.

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The resistance and immune escape of methicillin-resistant Staphylococcus aureus (MRSA) biofilms cause recalcitrant infections. Here, we design a targeting and synergizing cascade PDT with nutritional immunotherapy nanosystems (Arg-PCN@Gel) containing PCN-224 as PDT platform for providing reactive oxygen species (ROS), incorporating arginine (Arg) as nitric oxide (NO) donor to cascade with ROS to produce more lethal ONOO − and promote immune response, and coating with gelatin as targeting agent and persistent Arg provider. The nanosystems adhered to the autolysin of MRSA and inhibited Arg metabolism by down-regulating icdA and icaA . It suppressed polysaccharide intercellular adhesin and extracellular DNA synthesis to prevent biofilm formation. The NO broke mature biofilms and helped ROS and ONOO − penetrate into biofilms to inactivate internal MRSA. Arg-PCN@Gel drove Arg to enhance immunity via inducible NO synthase/NO axis and arginase/polyamine axis and achieve efficient target treatment in MRSA biofilm infections. The targeting and cascading PDT synergized with nutritional immunotherapy provide an effective promising strategy for biofilm-associated infections.

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Section: Resultsmentioning

confidence: 99%

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms

Zhang

Chen

et al. 2023

Sci. Adv.

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“…Importantly, DEGs in biofilm contains two of the largest regulons of Bmb9393, SarA, and CcpA. A recent paper by Bulock et al ( 2022 ) with the UAMS-1 strain showed that inactivation of CcpA reduced eDNA incorporation into the biofilm matrix (Bulock et al, 2022 ). Comparison of the 1,794 DEGs in biofilm against the non-redundant set of 1,151 target genes of the GRN resulted in 876 targets with altered expression in the biofilm, of which 370 were regulated by more than one TF and σ factor ( Table 3 ).…”

Section: Resultsmentioning

confidence: 99%

The gene regulatory network of Staphylococcus aureus ST239-SCCmecIII strain Bmb9393 and assessment of genes associated with the biofilm in diverse backgrounds

et al. 2023

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IntroductionStaphylococcus aureus is one of the most prevalent and relevant pathogens responsible for a wide spectrum of hospital-associated or community-acquired infections. In addition, methicillin-resistant Staphylococcus aureus may display multidrug resistance profiles that complicate treatment and increase the mortality rate. The ability to produce biofilm, particularly in device-associated infections, promotes chronic and potentially more severe infections originating from the primary site. Understanding the complex mechanisms involved in planktonic and biofilm growth is critical to identifying regulatory connections and ways to overcome the global health problem of multidrug-resistant bacteria.MethodsIn this work, we apply literature-based and comparative genomics approaches to reconstruct the gene regulatory network of the high biofilm-producing strain Bmb9393, belonging to one of the highly disseminating successful clones, the Brazilian epidemic clone. To the best of our knowledge, we describe for the first time the topological properties and network motifs for the Staphylococcus aureus pathogen. We performed this analysis using the ST239-SCCmecIII Bmb9393 strain. In addition, we analyzed transcriptomes available in the literature to construct a set of genes differentially expressed in the biofilm, covering different stages of the biofilms and genetic backgrounds of the strains.Results and discussionThe Bmb9393 gene regulatory network comprises 1,803 regulatory interactions between 64 transcription factors and the non-redundant set of 1,151 target genes with the inclusion of 19 new regulons compared to the N315 transcriptional regulatory network published in 2011. In the Bmb9393 network, we found 54 feed-forward loop motifs, where the most prevalent were coherent type 2 and incoherent type 2. The non-redundant set of differentially expressed genes in the biofilm consisted of 1,794 genes with functional categories relevant for adaptation to the variable microenvironments established throughout the biofilm formation process. Finally, we mapped the set of genes with altered expression in the biofilm in the Bmb9393 gene regulatory network to depict how different growth modes can alter the regulatory systems. The data revealed 45 transcription factors and 876 shared target genes. Thus, the gene regulatory network model provided represents the most up-to-date model for Staphylococcus aureus, and the set of genes altered in the biofilm provides a global view of their influence on biofilm formation from distinct experimental perspectives and different strain backgrounds.

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“…As a global regulator controlling S. aureus central metabolism and virulence, CcpA has been characterized to modulate S. aureus biofilm mainly through the icaA and cidA , which is responsible for PIA synthesis and eDNA release, respectively [ 14 , 15 , 26 ]. Interestingly, we found that transcription of both icaA and cidA did not significantly reduced in mutant ∆ ccpA compared to WT, with only a minor fold change of 1.29 and 1.07, respectively ( Figure 2 B).…”

Section: Resultsmentioning

confidence: 99%

“…Notably, the process of biofilm formation and structuring is tightly controlled, which correlated to the environmental cues and the dynamics within the bacterial community [ 8 ]. In S. aureus , the global regulator CcpA has been demonstrated to modulate biofilm development through induction of cidA and icaA expression, as well as by repression of the small noncoding RNA RsaI transcription [ 14 , 15 , 17 , 26 ]. Here, we found that CcpA directly inhibits the production of staphylokinase Sak, which ultimately affects the biofilm formation.…”

Section: Discussionmentioning

confidence: 99%

CcpA Regulates Staphylococcus aureus Biofilm Formation through Direct Repression of Staphylokinase Expression

et al. 2022

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Staphylococcus aureus represents a notorious opportunistic pathogen causing various infections in biofilm nature, imposing remarkable therapeutic challenges worldwide. The catabolite control protein A (CcpA), a major regulator of carbon catabolite repression (CCR), has been recognized to modulate S. aureus biofilm formation, while the underlying mechanism remains to be fully elucidated. In this study, the reduced biofilm was firstly determined in the ccpA deletion mutant of S. aureus clinical isolate XN108 using both crystal violet staining and confocal laser scanning microscopy. RNA-seq analysis suggested that sak-encoding staphylokinase (Sak) was significantly upregulated in the mutant ∆ccpA, which was further confirmed by RT-qPCR. Consistently, the induced Sak production correlated the elevated promoter activity of sak and increased secretion in the supernatants, as demonstrated by Psak-lacZ reporter fusion expression and chromogenic detection, respectively. Notably, electrophoretic mobility shift assays showed that purified recombinant protein CcpA binds directly to the promoter region of sak, suggesting the direct negative control of sak expression by CcpA. Double isogenic deletion of ccpA and sak restored biofilm formation for mutant ∆ccpA, which could be diminished by trans-complemented sak. Furthermore, the exogenous addition of recombinant Sak inhibited biofilm formation for XN108 in a dose-dependent manner. Together, this study delineates a novel model of CcpA-controlled S. aureus biofilm through direct inhibition of sak expression, highlighting the multifaceted roles and multiple networks regulated by CcpA.

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Interplay of CodY and CcpA in Regulating Central Metabolism and Biofilm Formation in Staphylococcus aureus

Cited by 10 publications

References 54 publications

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms

Targeting and arginine-driven synergizing photodynamic therapy with nutritional immunotherapy nanosystems for combating MRSA biofilms

The gene regulatory network of Staphylococcus aureus ST239-SCCmecIII strain Bmb9393 and assessment of genes associated with the biofilm in diverse backgrounds

CcpA Regulates Staphylococcus aureus Biofilm Formation through Direct Repression of Staphylokinase Expression

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