SarS, a SarA Homolog Repressible by
            <i>agr</i>
            , Is an Activator of Protein A Synthesis in
            <i>Staphylococcus aureus</i>

Cheung, Ambrose L.; Schmidt, Katherine A.; Bateman, Brian; Manna, A. La

doi:10.1128/iai.69.4.2448-2455.2001

Cited by 104 publications

(144 citation statements)

References 27 publications

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“…SarS has been reported to function as an activator of spa (surface protein A) expression (Cheung et al, 2001). This is consistent with the observation that expression of spa was also dramatically increased in UAMS-1 relative to RN6390 (Table 3).…”

Section: Resultssupporting

confidence: 80%

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Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Cassat

Dunman

Murphy³

et al. 2006

Microbiology

147

157

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The production of Staphylococcus aureus virulence factors is under the control of complex regulatory circuits. Most studies aimed at defining these regulatory networks have focused on derivatives of the strain NCTC 8325, most notably RN6390. However, all NCTC 8325 derivatives, including RN6390, possess an 11 bp deletion in rsbU. This deletion renders NCTC 8325 derivatives naturally sigma-factor-B deficient. Recent studies have shown that RN6390 is also deficient, in comparison to clinical isolates, with respect to biofilm formation, a process which is important for both pathogenesis and antimicrobial resistance. Based on these considerations, the authors carried out genome-scale transcriptional profiling, comparing RN6390 with the virulent rsbU-positive clinical isolate UAMS-1. The results revealed significant genome-wide differences in expression patterns between RN6390 and UAMS-1, and suggested that the overall transcriptional profile of UAMS-1 is geared toward expression of factors that promote colonization and biofilm formation. In contrast, the transcriptional profile of RN6390 was heavily influenced by RNAIII expression, resulting in a phenotype characterized by increased production of exoproteins, and decreased capacity to form a biofilm. The greater influence of agr in RN6390 relative to UAMS-1 was also evident when the transcriptional profile of UAMS-1 was compared with that of its isogenic sarA and agr mutants. Specifically, the results indicate that, in contrast to NCTC 8325 derivatives, agr plays a limited role in overall regulation of gene expression in UAMS-1, when compared with sarA. Furthermore, by defining the sarA regulon in a biofilm-positive clinical isolate, and comparing the results with transcriptional profiling experiments defining biofilm-associated gene expression patterns in the same strain, the authors identified a sarA-regulated operon (alsSD) that is also induced in biofilms, and demonstrated that mutation of alsSD results in reduced capacity to form a biofilm.

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Section: Resultssupporting

confidence: 80%

“…Expression of both sarS and spa is repressed by agr (Cheung et al, 2001). The fact that agr is expressed at lower levels in UAMS-1 and other clinical isolates, relative to RN6390, may therefore explain why sarS and spa are produced at elevated levels in these strains.…”

Section: Resultsmentioning

confidence: 93%

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Cassat

Dunman

Murphy³

et al. 2006

Microbiology

147

157

View full text Add to dashboard Cite

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“…2C). This feature may possibly explain how SarS, a 250-residue protein homologous to SarA (26), may function as a heterodimer-like monomer because it contains two sections, each highly similar to the SarR module and 125 residues long (26). The entire dimer can be described as three individual subdomain structures (Fig.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of the SarR protein from Staphylococcus aureus

Liu

Manna

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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The expression of virulence determinants in Staphylococcus aureus is controlled by global regulatory loci (e.g., sarA and agr). The sar (Staphylococcus accessory regulator) locus is composed of three overlapping transcripts (sarA P1, P3, and P2, transcripts initiated from the P1, P3, and P2 promoters, respectively), all encoding the 124-aa SarA protein. The level of SarA, the major regulatory protein, is partially controlled by the differential activation of the sarA promoters. We previously partially purified a 13.6-kDa protein, designated SarR, that binds to the sarA promoter region to down-modulate sarA transcription from the P1 promoter and subsequently SarA expression. SarR shares sequence similarity to SarA, and another SarA homolog, SarS. Here we report the 2.3 Å-resolution x-ray crystal structure of the dimeric SarR-MBP (maltose binding protein) fusion protein. The structure reveals that the SarR protein not only has a classic helix-turn-helix module for DNA binding at the major grooves, but also has an additional loop region involved in DNA recognition at the minor grooves. This interaction mode could represent a new functional class of the ''winged helix'' family. The dimeric SarR structure could accommodate an unusually long stretch of Ϸ27 nucleotides with two or four bending points along the course, which could lead to the bending of DNA by 90°or more, similar to that seen in the catabolite activator protein (CAP)-DNA complex. The structure also demonstrates the molecular basis for the stable dimerization of the SarR monomers and possible motifs for interaction with other proteins.

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“…Perhaps the most consistent transcriptional change observed for VISA strains is the downregulation of the spa gene (74,122,169,199,201,251,303). A possibly incomplete list of genes where the gene product has been shown to affect the transcription of spa includes agr (76,343), sarA (51,76,343), sarS (50), arlSR (85,86), sarT (304), srrAB (262), tcaR (200), mgrA (138), rot (240), ccpA (307), and sarZ (342). Potentially, a mutation in any of these regulatory genes could simultaneously increase vancomycin resistance and decrease protein A production.…”

Section: Molecular Mechanisms Of Resistancementioning

confidence: 99%

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

et al. 2010

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SUMMARY The emergence of vancomycin-intermediate Staphylococcus aureus (VISA) and heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) over the past decade has provided a challenge to diagnostic microbiologists to detect these strains, clinicians treating patients with infections due to these strains, and researchers attempting to understand the resistance mechanisms. Recent data show that these strains have been detected globally and in many cases are associated with glycopeptide treatment failure; however, more rigorous clinical studies are required to clearly define the contribution of hVISA to glycopeptide treatment outcomes. It is now becoming clear that sequential point mutations in key global regulatory genes contribute to the hVISA and VISA phenotypes, which are associated predominately with cell wall thickening and restricted vancomycin access to its site of activity in the division septum; however, the phenotypic features of these strains can vary because the mutations leading to resistance can vary. Interestingly, changes in the staphylococcal surface and expression of agr are likely to impact host-pathogen interactions in hVISA and VISA infections. Given the subtleties of vancomycin susceptibility testing against S. aureus, it is imperative that diagnostic laboratories use well-standardized methods and have a framework for detecting reduced vancomycin susceptibility in S. aureus.

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SarS, a SarA Homolog Repressible by agr , Is an Activator of Protein A Synthesis in Staphylococcus aureus

Cited by 104 publications

References 27 publications

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Transcriptional profiling of a Staphylococcus aureus clinical isolate and its isogenic agr and sarA mutants reveals global differences in comparison to the laboratory strain RN6390

Crystal structure of the SarR protein from Staphylococcus aureus

Reduced Vancomycin Susceptibility inStaphylococcus aureus, Including Vancomycin-Intermediate and Heterogeneous Vancomycin-Intermediate Strains: Resistance Mechanisms, Laboratory Detection, and Clinical Implications

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