Staphylococcal Biofilm Development: Structure, Regulation, and Treatment Strategies

Abstract

In many natural and clinical settings, bacteria are associated with some type of biotic or abiotic surface that enables them to form biofilms, a multicellular lifestyle with bacteria embedded in an extracellular matrix. Staphylococcus aureus and Staphylococcus epidermidis, the most frequent causes of biofilm-associated infections on indwelling medical devices, can switch between an existence as single free-floating cells and multicellular biofilms. During biofilm formation, cells first attach to a surface and then multiply to form microcolonies. They subsequently produce the extracellular matrix, a hallmark of biofilm formation, which consists of polysaccharides, proteins, and extracellular DNA. After biofilm maturation into three-dimensional structures, the biofilm community undergoes a disassembly process that leads to the dissemination of staphylococcal cells. As biofilms are dynamic and complex biological systems, staphylococci have evolved a vast network of regulatory mechanisms to modify and fine-tune biofilm development upon changes in environmental conditions. Thus, biofilm formation is used as a strategy for survival and persistence in the human host and can serve as a reservoir for spreading to new infection sites. Moreover, staphylococcal biofilms provide enhanced resilience toward antibiotics and the immune response and impose remarkable therapeutic challenges in clinics worldwide. This review provides an overview and an updated perspective on staphylococcal biofilms, describing the characteristic features of biofilm formation, the structural and functional properties of the biofilm matrix, and the most important mechanisms involved in the regulation of staphylococcal biofilm formation. Finally, we highlight promising strategies and technologies, including multitargeted or combinational therapies, to eradicate staphylococcal biofilms.

Keywords: Staphylococcus aureus; Staphylococcus epidermidis; biofilms; extracellular matrix; microbial communities; quorum sensing.

FIG 1

Staphylococcal biofilm cycle. During the first step of biofilm formation, planktonic staphylococcal cells attach to a surface with CWA proteins and WTAs (initial attachment). The production of PIA, eDNA, and adhesins to establish intercellular interactions is upregulated and leads to the formation of microcolonies on the surface (EPS production and cell proliferation). Cells within the growing biofilm express nucleases and PSMs, which are responsible for the formation of channels and towers in the matured biofilm. In the last step, the biofilm is dispersed by the action of PSMs and proteases, allowing the bacterial cells to detach from the biofilm to colonize new niches (biofilm structuring and cell detachment). The depiction of matrix components was inspired by Fig. 5 from the work of Hobley and colleagues (9).

FIG 2

Regulatory network of staphylococcal biofilm formation. Shown is a simplified overview of the Agr quorum sensing system, its regulatory interaction with the most important biofilm regulators (LytSR, SigB, CodY, SaeRS, MgrA, SarA, and Rot) and their influence on the molecular determinants of biofilm formation. Black arrows indicate stimulation, and red blunted arrows indicate repression.