Staphylococcal Biofilms

Abstract

Staphylococci, with the leading species Staphylococcus aureus and Staphylococcus epidermidis, are the most frequent causes of infections on indwelling medical devices. The biofilm phenotype that those bacteria adopt during device-associated infection facilitates increased resistance to antibiotics and host immune defenses. This review presents and discusses the molecular mechanisms contributing to staphylococcal biofilm development and their in-vivo importance. Furthermore, it summarizes current strategies for the development of therapeutics against staphylococcal biofilm-associated infection.

FIGURE 1

Staphylococcal biofilm development. Attachment of cells to a surface (in the case of surface-attached biofilms) occurs via hydrophobic interactions to an abiotic surface or via surface proteins that bind in a specific fashion to host matrix proteins covering an indwelling medical device. Growth of the biofilm in the proliferation/maturation stage is accompanied by the production of cell-cell adhesive matrix components (such as PIA, eDNA, and proteins), as well as disruptive factors (such as PSMs and degradative secreted enzymes). Those disruptive factors can also cause detachment, a process of great importance for the initiation of complications of biofilm-associated infection, such as bacteremia.

FIGURE 2

Predominant staphylococcal biofilm matrix components. The exopolysaccharide PIA (left), produced by many S. aureus and S. epidermidis isolates, is a β1-6-linked homopolymer of N-acetylglucosamine. It is synthesized in the cell by the combined activity of the membrane enzymes IcaA and IcaD and likely exported by IcaC. The extracellular surface-bound enzyme IcaB removes a certain percentage (∼15 to 20%) of N-acetyl moieties, which gives the otherwise neutral PIA molecule a positive net charge, anchoring PIA to the negatively charged cell surface. In addition to the ica biosynthetic genes icaADBC, the PIA biosynthesis locus also contains a regulatory gene, icaR. Several global regulators impact transcription from the icaR and icaADBC promoters. The accumulation-associated protein (Aap), which is present in S. epidermidis and has a homologue in S. aureus called SasG, is produced as a 220-kD precursor protein, from which the secreted protease SepA cleaves off the N-terminal A-repeat and lectin domains. It is anchored to the cell wall via sortase-catalyzed covalent linkage to lipid II. Mature Aap forms extended fibrils out of B repeat domains, whose polymerization is dependent on Zn²⁺ ions. Zn²⁺ is also required for the interconnection of Aap/SasG proteins from different cells, which can happen in an interspecies manner.

FIGURE 3

Staphylococcal biofilm-associated infection on medical devices. Mechanisms underlying staphylococcal device-associated infection are depicted in an exemplary fashion for an intravascular catheter-associated biofilm. Many of those are still hypothetical. Biofilm formation on a catheter may originate from bacteria introduced as a contamination during surgery/catheter insertion; those are believed to initiate biofilms on the catheter outside. Alternatively, biofilms in the lumen of the catheter can originate from bacteremia and other infection sites due to hematogenous seeding from those sites. Compared to planktonic growth, biofilms secrete fewer proinflammatory factors, which normally cause considerable responses by innate host defenses, such as phagocyte influx and AMP production. In addition to eliciting fewer such responses, the biofilm matrix provides a shelter from AMPs and phagocyte intrusion. S. aureus biofilms also attract myeloid-derived suppressor cells (MDSCs), which add to decreasing inflammatory responses, particularly phagocyte influx. Finally, internalization of bacteria, for example, by epithelial cells, can produce SCVs, which are prone to persist and cause recurrent infections.