Methicillin-resistant Staphylococcus aureus (MRSA) strains are known for their emergent multi-drug resistance phenotypes, implication in nosocomial infections and outbreaks worldwide, being commonly associated with hospital-acquired MRSA (HA-MRSA) and community-acquired MRSA (CA-MRSA) skin and soft tissue infections. S. aureus causes a wide spectrum of clinical symptoms, ranging from mild to life-threatening diseases; disease severity is determined by microorganism-related virulence factors and host condition. The ability of these strains to form microbial biofilms, one of the main pathogenicity factors, generates difficult medical problems, favored by the widespread use of large invasive medical procedures (probes, catheters, heart valves, prostheses). Contamination of these devices is associated with the risk of subsequent development of human infections. The knowledge of virulence and antibiotic resistance patterns of HA-MRSA and CA-MRSA and encoding genes are very important for supporting effective infection control measures and therapy of staphylococcal infections.
- Staphylococcus aureus
Staphylococci are commensal bacteria that form part of microbiota of human and animal skin and mucous membranes. Among more than 40 species of the genus,
In this chapter, we review some aspects related to resistance and virulence features in CA-MRSA and HA-MRSA strains, underlying the evolution of the highly successful community- and health care-associated lineages and their plasticity in ability to adapt to environmental changes.
Staphylococcus aureus resistance to antibiotics
Antistaphylococcal antibiotics are mainly targeting cell wall synthesis, proteins and nucleic acid synthesis, and different metabolic pathways. The large use of antibiotics, not only in the medical field but also in the agriculture has facilitated the evolution and spread of resistance genes . Bacterial resistance can be constitutive (mutations of the target genes, efflux pumps overexpression, etc.) or acquired by horizontal gene transfer via various mobile genetic elements like plasmids, transposons, bacteriophages, pathogenicity islands, and staphylococcal cassette chromosomes . Plasmids and staphylococcal cassette chromosomes in particular have played a central role in conferring resistance to β-lactam antibiotics and vancomycin .
Penicillin resistance is conferred by β-lactamase, an extracellular enzyme encoded by
Methicillin resistance requires the presence of the chromosomally localized
PBPs are membrane-bound enzymes that are used in cross-linkage of peptidoglycan chains by catalyzing the transpeptidation reaction . PBP2a has a low affinity for β-lactam antibiotics and thus methicillin resistance also grants resistance to all β-lactam antibiotics .
Eleven types of SCC
There have been revealed molecular differences between CA-MRSA and HA-MRSA strains regarding the types of SCC
HA-MRSA strains seldom carry the genes for the Panton-Valentine leukocidin (PVL). CA-MRSA isolates carry smaller SCC
There have been revealed that the deletion of the gene encoding PBP 4 in two common CA-MRSA isolates, USA300 and USA400, resulted in a 16-fold reduction in oxacillin and nafcillin resistance in these particular stains. These studies suggest that PBP 4 is a significant target for the discovery of agents effective against CA-MRSA .
There have been also reported CA-MRSA strains positive for
The emergence/re-emergence of successful
Most of the nosocomial MRSA infections are caused by five major lineages that circulate internationally: CC5, CC8, CC22, CC45 and CC30 .
ST1 pulsotype USA 400—represented the most frequently CA-MRSA clone in the United States after 1990s; was characterized by carrying SCC
MRSA infections in the community can also be caused by livestock-associated MRSA (LA-MRSA). LA-MRSA is initially associated with livestock and differs from genotypic HA-MRSA and genotypic CA-MRSA in its genomic traits. CC9 clonal complex (LA-MRSA) is most frequent among livestock in Asia . In the USA, ST5 (MRSA) was isolated from pigs . CC1 (MRSA) is prevalent in Romanian nosocomial infections and has low host specificity .
The quinolones act on DNA gyrase, which relieves DNA supercoiling, and topoisomerase IV, which separates concatenated DNA strands. Resistance to quinolones results from the stepwise acquisition of chromosomal mutations . Quinolone affinity is reduced by changes of the amino acids in the enzyme-DNA complex (quinolone resistance-determining region [QRDR]). The most common sites of resistance mutations are GyrA subunit in gyrase and ParC (GrlA in
An additional mechanism of resistance in
The molecular mechanisms that underlie development of hVISA are incompletely defined. Fundamental characteristics of the VISA phenotype include increased cell wall thickness, caused by differentially regulated cell wall biosynthesis and stimulatory pathways [15, 41], reduced cross-linking of peptidoglycan, decreased autolytic activity of the enzymes responsible to cell-wall turnover [15, 42], altered surface protein profile, dysfunction of the
Molecular basis of the VISA phenotype is not fully understood but several genes/mutations are known to contribute to its development. The mutations within genes encoding two-component regulatory systems, such as
The VISA strains produce considerable amounts of peptidoglycan and this generates thicker, irregularly shaped cell walls. They also expose more D-Ala-D-Ala residues available to bind and trap vancomycin which acts as a further impediment to drug molecules reaching their target on the cytoplasmic membrane .
Complete vancomycin resistance in
Staphylococcus aureus adhesion and biofilm development
The broad range of infections caused by
The initialization of the colonization process is started by the attachment of
Staphylococcal cell wall-anchored (CWA) proteins are secreted by the Sec system and share a C-terminal cell wall anchoring motif, hydrophobic domain and positively charged domain . Foster et al.  proposed to classify the Staphylococcal CWA proteins into four groups based on structural motifs: MSCRAMMs (microbial surface component recognizing adhesive matrix molecules), the NEAT motif family, the three-helical bundle family and the G5-E repeat family. All of these types of CWA proteins are involved in staphylococcal biofilm formation. MSCRAMMs are adhesins that contain at least two IgG-like folds and employ a ligand binding mechanism called dock, lock and latch . MSCRAMMS are composed of a binding domain, a cell wall spanning domain and a domain for the covalent or non-covalent attachment. These adhesins can bind one or more human proteins (collagen—mostly via Cna, fibronectin—via FnbAB, fibrinogen—via ClfAB and Fib) [51, 52].
The Staphylococcal MSCRAMMs are the Clf-Sdr family proteins, including bone sialoprotein-binding protein (Bbp), the fibronectin-binding proteins (FnBPs) and collagen adhesion (CNA) . The Clf-Sdr family consists of Clumping factor A (ClfA), clumping factor B (ClfB) and the Sdr proteins. ClfA and ClfB are fibrinogen-binding proteins in
The NEAT motif family consists of the iron-regulated surface determinant (Isd) proteins who bind heme or hemoglobin, facilitating its transport into the bacterial cell, and they are up-regulated in iron-limiting conditions .
The sole three-helical bundle cell wall-anchored protein is Staphylococcal Protein A (SpA), which is present in all strains of
G5-E Repeat Family: Aap/SasG—G5-E repeats are found in cell wall-anchored adhesins in Gram-positive organisms (are named after the five conserved glycine residues in each repeat).
Uncategorized CWA Proteins—the remaining uncategorized cell wall-anchored proteins are Bap and several Sas proteins, including SasA/SraP. SasX is another cell wall-anchored adhesin that has been shown to play an important role in virulence .
Surface-associated proteinaceous adhesins—autolysins AtlA and AtlE are found in
Non-proteinaceous surface-associated adhesins—wall teichoic acids and lipoteichoic acids have been shown to play a role in adhesion, colonization of host cells and biofilm formation. Wall teichoic acids are covalently linked to the peptidoglycan and consist of alternating phosphate and ribitol, while lipoteichoic acids attach to the outer leaflet of the cell membrane and have alternating phosphate and glycerol .
The polysaccharide intercellular adhesion (PIA) is a secreted polysaccharide that is synthesized by the
One of the reasons the staphylococcal infections are difficult to eradicate is the bacteria’s ability to develop community structures known as biofilms by attaching to different surfaces (tissues, catheters and medical devices), and often occur in areas of the body that are not easily accessible for treatment .
Biofilm is an assemblage of microbial cells that are irreversibly associated to a surface and embedded in a protective extracellular polymeric matrix. Biofilm-associated organisms have proteins production and genes expression modification compared to their planktonic counterparts .
Biofilm formation can be divided into three major stages: initial attachment, development/maturation of the biofilm and dispersion.
During initial attachment, bacteria adhere to the available surface and in case of abiotic one its conditioning is important through various physiochemical parameters: chemical composition of the material, hydrophobicity, electrostatic charges, surface energy and surface roughness and in the case of biotic adhesion: serum and tissue protein adsorption .
The final stage of biofilm development is the detachment of cells from the biofilm colony and their dispersal into the environment, which contributes to biological dispersal, bacterial survival and disease transmission. Like other stages of biofilm development, dispersal is a complex process that involves numerous environmental signals, signal transduction pathways and effectors .
The biofilm matrix is a complex structure that contains extracellular DNA (eDNA), both from lysed bacteria and potentially from host neutrophil cell death , proteinaceous adhesins directly associated with bacteria in the biofilm or free in the biofilm matrix , recycled cytoplasmic proteins that moonlight as components of the extracellular matrix , the extracellular polysaccharide intercellular adhesin (PIA), teichoic acids . The matrix can impede the access of certain types of immune defenses, such as macrophages .
Cell adhesion and subsequently biofilm formation are processes mediated by covalently and non-covalently cell wall proteins and non-protein factors. For
Switching between planktonic and biofilm-forming modes represents a major life style change for microbes, and has been shown to be a tightly regulated process  through quorum sensing (QS) which is a cell-cell communication mechanism in which bacteria secrete and sense small diffusible molecules called autoinducers (AIs) to coordinate social activities, such as bioluminescence, biofilm formation, swarming behavior, antibiotic production and virulence factor secretion .
Staphylococcal biofilm formation is affected by growth conditions (e.g., NaCl, glucose, human plasma, etc.) and is controlled by multiple global regulators such as SarA, Agr, SigB and Sae. The Sae-regulon includes both the factors promoting biofilm formation (i.e., Coa, Emp, Eap, FnBPA, FnBPB, Hla and Hlb) and biofilm dispersal factors (nuclease and proteases) and depending on growth conditions and strain backgrounds, the Sae system could affect biofilm formation either positively or negatively .
Bacteria in biofilms can tolerate ten to thousand fold higher levels of antibiotics than the genetically equivalent planktonic bacteria. Staphylococcal biofilms cause biomaterial-associated infections which do not respond to antimicrobial treatment often requiring removal of the same leading to substantial morbidity and mortality. It has also been observed that biofilms harbour persister cells and small colony variants , whereas planktonic persisters are eliminated by the immune system
Staphylococcus aureus soluble virulence factors
α-Hemolysin is the most characterized virulence factor of
The γ hemolysin variant and leukocidin E-D gene, as well as other genes encoding exotoxins, were detected evenly in HA and CA-MRSA strains, while sec and sek genes were found only in CA-MRSA strains .
β-Hemolysin is a neutral sphingomyelinase, it hydrolyses a plasma membrane lipid—sphingomyelin and does not form pores in the plasma cell. β-hemolysin’s enzymatic activity is required for its hemolytic activity .
δ-Hemolysin is a small amphipathic α-helix-structured peptide (26 AA). Its hemolytic activity can be realized by forming transmembrane pores, affecting the membrane curvature or acting as detergent to solubilize the membrane .
This family of cytotoxic peptides includes new peptides termed PSM. PSMs represent a secreted α-helical peptides produced by different
Protein A prevents the opsonization and phagocytosis by ineffectually binding the Fc region of IgG. It also initiates a proinflammatory cascade in the airway by activating tumor necrosis factor receptor 1 (TNFR1) and B cells in concert with other ligands. MRSA strains with certain
PVL is a bi-component exotoxin transmitted by bacteriophages, encoded by two genes,
α-Toxin lyses immune cells like macrophages and lymphocytes, alters platelet morphology, which increased thrombotic events associated with
Arginine catabolic mobile element (ACME) is a large MGE that plays an important role in the growth, transmission and pathogenesis of CA-MRSA. Two main gene clusters identified as
5. Regulation of virulence factors expression in
Among the regulatory elements, the Agr (the accessory gene regulator) system is the only characterized QS system in
Sigma B (SigB) is an alternative sigma factor of RNA polymerase that is activated in stress response and modifies gene expression. SigB upregulates the expression of different factors involved in initial stages of biofilm formation like coagulase, FnBPA and clumping factor . It also controls negative factors that are associated with a planktonic phenotype and seeding dispersal, including enterotoxin B, cysteine protease (SplB), serine protease (SplA), the metalloprotease Aur, staphopain, leukotoxin D and β-hemolysin .
We thank Professor Mariana Carmen Chifiriuc for the kind guidance and supervision.
Conflict of interest
There is no conflict of interest.
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