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PubMed2006

Sticky connections: extracellular matrix protein recognition and integrin-mediated cellular invasion by Staphylococcus aureus.

Staphylococcus aureus is a leading cause of hospital-acquired and often persistent infections. A key feature of pathogenic S. aureus is the expression of an array of extracellular matrix-binding proteins. In particular, the fibronectin-binding proteins FnBP-A and FnBP-B afford the pathogen the ability to connect to cellular integrins and to trigger internalization into host cells. Recent work has highlighted the role of host cell invasion in the pathogenesis of S. aureus, the structure-function relationship of FnBPs, and the host factors required to allow bacterial uptake. Understanding the invasive capacity of S. aureus should open up new avenues to control this microorganism in diverse disease settings.

Adhesins, Bacterial↗

PubMed2000

Longitudinal evaluation of CD4+ and CD8+ peripheral blood and mammary gland lymphocytes in cows experimentally inoculated with Staphylococcus aureus.

Staphylococcus aureus is a major pathogen associated with mastitis, a disease affecting both women and dairy cows. The longitudinal profiles of bovine peripheral blood and mammary gland lymphocyte phenotypes in response to S. aureus-induced mastitis were investigated in dairy cows. Increased percentage of CD4 lymphocytes in the mammary gland between 1 and 8 days post-inoculation, increased milk CD4 protein density per cell between 1-8 days post-inoculation, and a statistically significant negative correlation between post-inoculation bacterial counts in milk and blood lymphocyte CD4 protein density were found. Together with blood and milk leukocyte counts, the milk lymphocyte CD4/CD8 ratio and the milk lymphocyte CD4 protein density were more informative indicators than milk somatic cell counts and bacteriology for identification of early vs. late inflammatory phases. These findings suggest that CD4+ lymphocytes play a protective role in the early stages of S. aureus-induced mastitis.

Animals↗

PubMed1999

4,4'-diapophytoene desaturase: catalytic properties of an enzyme from the C(30) carotenoid pathway of Staphylococcus aureus.

Staphylococcus aureus synthesizes C(30) carotenoids. Their formation involves the introduction of three double bonds, which is catalyzed by a single enzyme. This enzyme, 4,4'-diapophytoene desaturase from S. aureus, was overexpressed in Escherichia coli and purified in one step by affinity chromatography, and then the protein was characterized with respect to substrate specificity, cofactor requirement, and oligomerization.

Bacterial Proteins↗

PubMed1998

Species-specific and ubiquitous-DNA-based assays for rapid identification of Staphylococcus aureus.

Staphylococcus aureus is the cause of serious infections in humans, including endocarditis, deep-seated abscesses, and bacteremia, which lead to toxic and septic shock syndromes. Rapid and direct identification of this bacterium specifically and ubiquitously directly from clinical specimens would be useful in improving the diagnosis of S. aureus infections in the clinical microbiology laboratory. A wide variety of kits based on biochemical characteristics efficiently identify S. aureus, but the rapidity and the accuracy of each of these methods combined with testing of clinically relevant antibiotic resistance genes need to be improved. On the basis of hybridization assays with randomly selected clones from an S. aureus genomic library, we have identified a chromosomal DNA fragment which is specific for S. aureus and which detected all 82 S. aureus isolates tested. This 442-bp fragment was sequenced and was used to design a set of PCR amplification primers. The PCR assay was also specific and ubiquitous for the identification from bacterial cultures of 195 clinical strains of S. aureus isolated from a variety of anatomical sites and obtained from hospitals throughout the world. The PCR assay that we have developed is simple and can be performed in about 1 h. This DNA-based test provides a novel diagnostic tool for the diagnosis of S. aureus infections.

Cloning, Molecular↗

PubMed2006

Vaccine assembly from surface proteins of Staphylococcus aureus.

Staphylococcus aureus is the most common cause of hospital-acquired infection. Because of the emergence of antibiotic-resistant strains, these infections represent a serious public health threat. To develop a broadly protective vaccine, we tested cell wall-anchored surface proteins of S. aureus as antigens in a murine model of abscess formation. Immunization with four antigens (IsdA, IsdB, SdrD, and SdrE) generated significant protective immunity that correlated with the induction of opsonophagocytic antibodies. When assembled into a combined vaccine, the four surface proteins afforded high levels of protection against invasive disease or lethal challenge with human clinical S. aureus isolates.

Abscess↗

PubMed1999

Apoptosis observed in BALB/3T3 cells having ingested Staphylococcus aureus.

Staphylococcus aureus was previously shown to be internalized by murine fibroblast. We examined the intracellular events of S. aureus ingested by BALB/3T3 cells. After uptake of strains A191 and A151, isolates from atopic lesion, and a laboratory strain, Cowan I, for 1 hr, BALB/3T3 cells were incubated with 1.25 microg/ml lysostaphin. Laddering of the DNA in multiples of approximately 180 bp occurred within 4 hr following bacterial addition in BALB/3T3 cells infected with A191 and within 18 hr in BALB/3T3 cells infected with A151: histochemical staining by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling method revealed that the rate of the fragmentation of nucleic DNA in Cowan I-infected BALB/3T3 cells at 21 hr following bacterial addition was 0.52 +/- 0.25%, significantly higher than that in the control cells. Transmission electron micrographs of BALB/3T3 cells at 4 hr following A191 addition showed that the apoptotic features, including electron-dense nucleus and plasma membrane blebbing, occurred in some cells in which many staphylococci escaped the endosome and went on to cell division. At the same time, A151 organisms enclosed with endosome membrane were static in the intact BALB/3T3 cells. The significant increase of A191 was confirmed by counting intracellular live bacteria during 2- to 6-hr incubation. These results suggest that internalized S. aureus escapes the endosome, multiplies and induces apoptosis in the fibroblast cell.

3T3 Cells↗

PubMed2004

In vitro assembly of a complete, pentaglycine interpeptide bridge containing cell wall precursor (lipid II-Gly5) of Staphylococcus aureus.

Staphylococcus aureus peptidoglycan is cross-linked via a characteristic pentaglycine interpeptide bridge. Genetic analysis had identified three peptidyltransferases, FemA, FemB and FemX, to catalyse the formation of the interpeptide bridge, using glycyl t-RNA as Gly donor. To analyse the pentaglycine bridge formation in vitro, we purified the potential substrates for FemA, FemB and FemX, UDP-MurNAc-pentapeptide, lipid I and lipid II and the staphylococcal t-RNA pool, as well as His-tagged Gly-tRNA-synthetase and His-tagged FemA, FemB and FemX. We found that FemX used lipid II exclusively as acceptor for the first Gly residue. Addition of Gly 2,3 and of Gly 4,5 was catalysed by FemA and FemB, respectively, and both enzymes were specific for lipid II-Gly1 and lipid II-Gly3 as acceptors. None of the FemABX enzymes required the presence of one or two of the other Fem proteins for activity; rather, bridge formation was delayed in the in vitro system when all three enzymes were present. The in vitro assembly system described here will enable detailed analysis of late, membrane-associated steps of S. aureus peptidoglycan biosynthesis.

Bacterial Proteins↗

PubMed1989

Emergence of methicillin-resistant clones from cephamycin-resistant Staphylococcus aureus.

Staphylococcus aureus strains specifically resistant to cephamycin antibiotics have been found among recent clinical isolates. These strains formed penicillin-binding protein (PBP) 2' and became phenotypically resistant to methicillin after induction with cefoxitin. Other cephamycin-type antibiotics also induced methicillin-resistance, whereas non-cephamycin-type cephalosporins such as cefmenoxime and ceftizoxime did not do so. The clones that constitutively synthesized PBP 2' arose from the cephamycin-resistant strains at a frequency of 10(-5). They were indistinguishable from clinically isolated methicillin-resistant S. aureus (MRSA). Cephamycin-resistant S. aureus may be a source for emerging MRSA.

Bacterial Proteins↗

PubMed2005

Why are pathogenic staphylococci so lysozyme resistant? The peptidoglycan O-acetyltransferase OatA is the major determinant for lysozyme resistance of Staphylococcus aureus.

Staphylococcus species belong to one of the few bacterial genera that are completely lysozyme resistant, which greatly contributes to their persistence and success in colonizing the skin and mucosal areas of humans and animals. In an attempt to discover the cause of lysozyme resistance, we identified a gene, oatA, in Staphylococcus aureus. The corresponding oatA deletion mutant had an increased sensitivity to lysozyme. HPLC and electrospray ionization tandem mass spectrometry analyses of the cell wall revealed that the muramic acid of peptidoglycan of the wild-type strain was O-acetylated at C6-OH, whereas the muramic acid of the oatA mutant lacked this modification. The complemented oatA mutant was lysozyme resistant. We identified the first bacterial peptidoglycan-specific O-acetyltransferase in S. aureus and showed that OatA, an integral membrane protein, is the molecular basis for the high lysozyme resistance in staphylococci.

Acetylation↗

PubMed2007

Genes required for glycolipid synthesis and lipoteichoic acid anchoring in Staphylococcus aureus.

Staphylococcus aureus lipoteichoic acid (LTA) is composed of a linear 1,3-linked polyglycerolphosphate chain and is tethered to the bacterial membrane by a glycolipid (diglucosyl-diacylglycerol [Glc2-DAG]). Glc2-DAG is synthesized in the bacterial cytoplasm by YpfP, a processive enzyme that transfers glucose to diacylglycerol (DAG), using UDP-glucose as its substrate. Here we present evidence that the S. aureus alpha-phosphoglucomutase (PgcA) and UTP:alpha-glucose 1-phosphate uridyltransferase (GtaB) homologs are required for the synthesis of Glc2-DAG. LtaA (lipoteichoic acid protein A), a predicted membrane permease whose structural gene is located in an operon with ypfP, is not involved in Glc2-DAG synthesis but is required for synthesis of glycolipid-anchored LTA. Our data suggest a model in which LtaA facilitates the transport of Glc2-DAG from the inner (cytoplasmic) leaflet to the outer leaflet of the plasma membrane, delivering Glc2-DAG as a substrate for LTA synthesis, thereby generating glycolipid-anchored LTA. Glycolipid anchoring of LTA appears to play an important role during infection, as S. aureus variants lacking ltaA display defects in the pathogenesis of animal infections.

Animals↗

PubMed2004

Involvement of SirABC in iron-siderophore import in Staphylococcus aureus.

Staphylococcus aureus SirA was previously identified as a lipoprotein, and SirB and SirC are thought to encode the transmembrane domains of an ABC transporter. Sir proteins show similarity to iron-siderophore transporters in several bacteria. Here, we show that the iron-regulated sirABC operon is divergently transcribed from the sbn operon that encodes enzymes involved in the synthesis of staphylobactin, a recently described siderophore produced by S. aureus. Mutation of either sirA or sirB increased the resistance of iron-starved S. aureus to streptonigrin and resulted in compromised growth in iron-restricted, but not iron-rich, media. We also demonstrated that sirA and sirB mutants are compromised in the ability to transport iron complexed to staphylobactin but are not compromised for uptake of other iron complexes, such as ferric hydroxamates, ferric enterobactin, or ferric citrate. SirA- and SirB-deficient S. aureus, however, retain the ability to produce staphylobactin. Moreover, we found that transcription from the sbn operon was increased, relative to the wild type, in both sirA and sirB knockout strains, likely in response to an increased level of iron starvation in these cells. These results provide evidence of a role for these proteins in iron import in S. aureus and for full fitness of the bacterium in iron-restricted environments and demonstrate a function for S. aureus genes encoding proteins involved in the transport of an endogenously produced siderophore.

ATP-Binding Cassette Transporters↗

PubMed1994

Virulence factors involved in the pathogenesis of bovine intramammary infections due to Staphylococcus aureus.

Staphylococcus aureus is a major causative agent of intramammary infections in dairy cows. In this report, the pathogenesis of these infections is described. The potential role in virulence of S. aureus surface components (adhesins, protein A and capsular polysaccharides), toxins, extracellular enzymes and coagulase, and perspectives for the development of an efficient vaccine are discussed.

Animals↗

PubMed2004

Role of biofilm-associated protein bap in the pathogenesis of bovine Staphylococcus aureus.

Staphylococcus aureus is a common cause of intramammary infections, which frequently become chronic, associated with the ability of the bacteria to produce biofilm. Here, we report a relationship between the ability to produce chronic bovine mastitis and biofilm formation. We have classified bovine mastitis S. aureus isolates into three groups based on the presence of particular genetic elements required for biofilm formation: group 1 (ica(+) bap(+)), group 2 (ica(+), bap negative), and group 3 (ica negative, bap negative). Overall, animals naturally infected with group 1 and 2 isolates had a lower milk somatic cell count than those infected with isolates of group 3. In addition, Bap-positive isolates were significantly more able to colonize and persist in the bovine mammary gland in vivo and were less susceptible to antibiotic treatments when forming biofilms in vitro. Analysis of the structural bap gene revealed the existence of alternate forms of expression of the Bap protein in S. aureus isolates obtained under field conditions throughout the animal's life. The presence of anti-Bap antibodies in serum samples taken from animals with confirmed S. aureus infections indicated the production of Bap during infection. Furthermore, disruption of the ica operon in a bap-positive strain had no effect on in vitro biofilm formation, a finding which strongly suggested that Bap could compensate for the deficiency of the PIA/PNAG product (a biofilm matrix polysaccharide). Altogether, these results demonstrate that, in the bovine intramammary gland, the presence of Bap may facilitate a biofilm formation connected with the persistence of S. aureus.

Animals↗

PubMed2001

Identification and characterization of fhuD1 and fhuD2, two genes involved in iron-hydroxamate uptake in Staphylococcus aureus.

Staphylococcus aureus can utilize several hydroxamate siderophores for growth under iron-restricted conditions. Previous findings have shown that S. aureus possesses a cytoplasmic membrane-associated traffic ATPase that is involved in the specific transport of iron(III)-hydroxamate complexes. In this study, we have identified two additional genes, termed fhuD1 and fhuD2, whose products are involved in this transport process in S. aureus. We have shown that fhuD2 codes for a posttranslationally modified lipoprotein that is anchored in the cytoplasmic membrane, while the deduced amino acid sequence predicts the same for fhuD1. The predicted FhuD1 and FhuD2 proteins share 41.0% identity and 56.4% total similarity with each other, 45.9 and 49.1% total similarity with the FhuD homolog in Bacillus subtilis, and 29.3 and 24.6% total similarity with the periplasmic FhuD protein from Escherichia coli. Insertional inactivation and gene replacement of both genes showed that while FhuD2 is involved in the transport of iron(III) in complex with ferrichrome, ferrioxamine B, aerobactin, and coprogen, FhuD1 shows a more limited substrate range, capable of only iron(III)-ferrichrome and iron(III)-ferrioxamine B transport in S. aureus. Nucleotide sequences present upstream of both fhuD1 and fhuD2 predict the presence of consensus Fur binding sequences. In agreement, transcription of both genes was negatively regulated by exogenous iron levels through the activity of the S. aureus Fur protein.

Amino Acid Sequence↗

PubMedDate not supplied

Effect of Varidase (streptokinase) on biofilm formed by Staphylococcus aureus.

Staphylococcus aureus forms a fibrin-rich biofilm in the presence of plasma which is highly resistant to attack by the human immune system and to chemotherapy. Varidase, composed mainly of streptokinase, is used for hydrolyzing clots. In this study, we attempted to destroy the biofilm of S. aureus with Varidase and to apply this drug in the treatment of staphylococcal infections. Four clinical isolates were used in the experiments. These organisms formed a several-millimeter-thick biofilm on type IV collagen coated coverslips in trypticase soy broth containing 50% human plasma. The biofilm was composed of bacterial cell which adhered to fibrillar fibers and of sediment derived from plasma. 10,000 U/ml of Varidase, the dose which is used clinically, removed the sediment and reduced the number of live bacteria in biofilms to less than 20% of control. 200 U/ml of Varidase was also effective against biofilms of the organisms. An equal combination of Varidase and ofloxacin had an additive effect on the bacteria. The results of this study demonstrate that Varidase is highly effective in destroying biofilms of S. aureus in vitro and suggest that this drug would be useful for treating staphylococcal infections.

Biofilms↗

PubMed1987

Ocular immunity to Staphylococcus aureus.

Staphylococcus aureus is an important cause of infectious disease of the eye and hypersensitivity lesions of the cornea including phlyctenules and catarrhal infiltrates. Because little is known about ocular immunity to S. aureus, we measured antibody levels to ribitol teichoic acid, the major antigenic determinant of S. aureus, in rabbit serum and tears using an enzyme-linked immunosorbent assay after immunization with S. aureus antigens using the following routes: intradermal injection of cell wall mixed with complete Freund's adjuvant, subconjunctival injection of cell wall mixed with complete Freund's adjuvant, topical application of cell wall to the eye, and topical application of viable S. aureus to the eye. All four immunization groups showed an IgG antibody response to ribitol teichoic acid in serum and tears with the highest titers in serum found after intradermal immunization with cell wall and the highest titers in tears found after topical application of S. aureus. All four immunization routes showed an IgA antibody response to ribitol teichoic acid in tears with the highest titers found after subconjunctival immunization with cell wall. There was no IgA response to ribitol teichoic acid in serum in any group. The results of this study suggest that ocular immune responses to S. aureus may be influenced by exposure to staphylococcal antigens not only in the external eye but also at sites remote from the eye.

Administration, Topical↗

PubMed2006

An oxidation-sensing mechanism is used by the global regulator MgrA in Staphylococcus aureus.

Staphylococcus aureus is a human pathogen responsible for most wound and hospital-acquired infections. The protein MgrA is both an important virulence determinant during infection and a regulator of antibiotic resistance in S. aureus. The crystal structure of the MgrA homodimer, solved at 2.86 A, indicates the presence of a unique cysteine residue located at the interface of the protein dimer. We discovered that this cysteine residue can be oxidized by various reactive oxygen species, such as hydrogen peroxide and organic hydroperoxide. Cysteine oxidation leads to dissociation of MgrA from DNA and initiation of signaling pathways that turn on antibiotic resistance in S. aureus. The oxidation-sensing mechanism is typically used by bacteria to counter challenges of reactive oxygen and nitrogen species. Our study reveals that in S. aureus, MgrA adopts a similar mechanism but uses it to globally regulate different defensive pathways.

Bacterial Proteins↗

PubMed2023

Serine-threonine phosphoregulation by PknB and Stp contributes to quiescence and antibiotic tolerance in Staphylococcus aureus.

Staphylococcus aureus can cause infections that are often chronic and difficult to treat, even when the bacteria are not antibiotic resistant because most antibiotics act only on metabolically active cells. Subpopulations of persister cells are metabolically quiescent, a state associated with delayed growth, reduced protein synthesis, and increased tolerance to antibiotics. Serine-threonine kinases and phosphatases similar to those found in eukaryotes can fine-tune essential bacterial cellular processes, such as metabolism and stress signaling. We found that acid stress-mimicking conditions that S. aureus experiences in host tissues delayed growth, globally altered the serine and threonine phosphoproteome, and increased threonine phosphorylation of the activation loop of the serine-threonine protein kinase B (PknB). The deletion of stp, which encodes the only annotated functional serine-threonine phosphatase in S. aureus, increased the growth delay and phenotypic heterogeneity under different stress challenges, including growth in acidic conditions, the intracellular milieu of human cells, and abscesses in mice. This growth delay was associated with reduced protein translation and intracellular ATP concentrations and increased antibiotic tolerance. Using phosphopeptide enrichment and mass spectrometry-based proteomics, we identified targets of serine-threonine phosphorylation that may regulate bacterial growth and metabolism. Together, our findings highlight the importance of phosphoregulation in mediating bacterial quiescence and antibiotic tolerance and suggest that targeting PknB or Stp might offer a future therapeutic strategy to prevent persister formation during S. aureus infections.

Animals↗