Staphylococcus aureus, Antibiotic Resistance, and the Interaction with Human Neutrophils

Abstract

Significance:Staphylococcus aureus is among the leading causes of bacterial infections worldwide. The high burden of S. aureus among human and animal hosts, which includes asymptomatic carriage and infection, is coupled with a notorious ability of the microbe to become resistant to antibiotics. Notably, S. aureus has the ability to produce molecules that promote evasion of host defense, including the ability to avoid killing by neutrophils. Recent Advances: Significant progress has been made to better understand S. aureus-host interactions. These discoveries include elucidation of the role played by numerous S. aureus virulence molecules during infection. Based on putative functions, a number of these virulence molecules, including S. aureus alpha-hemolysin and protein A, have been identified as therapeutic targets. Although it has not been possible to develop a vaccine that can prevent S. aureus infections, monoclonal antibodies specific for S. aureus virulence molecules have the potential to moderate the severity of disease. Critical Issues: Therapeutic options for treatment of methicillin-resistant S. aureus (MRSA) are limited, and the microbe typically develops resistance to new antibiotics. New prophylactics and/or therapeutics are needed. Future Directions: Research that promotes an enhanced understanding of S. aureus-host interaction is an important step toward developing new therapeutic approaches directed to moderate disease severity and facilitate treatment of infection. This research effort includes studies that enhance our view of the interaction of S. aureus with human neutrophils. Antioxid. Redox Signal. 34, 452-470.

Keywords: CA-MRSA; MRSA; PMN; Staphylococcus aureus; antibiotic resistance; neutrophil.

Figures

FIG. 1.

Staphylococcus aureus. Scanning electron micrograph of S. aureus (yellow) bound to a human neutrophil (blue).

FIG. 2.

Interaction of S. aureus penicillinase with penicillin and methicillin. Penicillinase hydrolyzes the amide bond (highlighted in red) of the β-lactam ring of penicillin and ampicillin (A). Methicillin is resistant to cleavage by S. aureus penicillinase (a β-lactamase) due to the presence of an ortho-dimethoxyphenyl group (highlighted in green) that sterically hinders the enzyme from hydrolyzing its target amide bond (B).

FIG. 3.

S. aureus methicillin resistance is conferred by PBP2a, which has reduced affinity for methicillin. MSSA (left side) contains PBP1–4 that are readily bound by methicillin, a process that inhibits peptidoglycan and cell wall synthesis. By comparison, PBP2a has reduced affinity for methicillin, and thus PBP2a can participate in cell wall synthesis. MSSA, methicillin-susceptible S. aureus; PBP2a, penicillin-binding protein 2a; PBP1–4, penicillin binding proteins 1–4.

FIG. 4.

Antibacterial action of vancomycin and mechanism of resistance. Vancomycin inhibits cell wall synthesis by binding to D-Ala-D-Ala residues of peptidoglycan precursor molecules (A). In vancomycin-resistant S. aureus, D-Ala-D-Ala residues of the peptidoglycan precursor molecule are replaced by D-Ala-D-Lac residues, which do not bind vancomycin. Peptidoglycan cross-linking occurs normally (B).

FIG. 5.

Neutrophil phagocytosis and activation. Neutrophil phagocytosis of S. aureus and subsequent intracellular microbicidal processes. Specific and azurophilic granules fuse with the phagosome, thereby enriching the lumen of the vacuole with antimicrobial peptides and proteins. In addition, the NADPH oxidase assembles at the phagosome membrane and produces superoxide, which is converted to other ROS. CR, complement receptor; FcR, antibody Fc receptor; MPO, myeloperoxidase; PRR, pattern recognition receptor; ROS, reactive oxygen species.

FIG. 6.

Possible outcomes of neutrophil phagocytosis of S. aureus. Efferocytosis is the phagocytosis of cells undergoing apoptosis. PICD, phagocytosis-induced cell death.