Force matters in hospital-acquired infections
(2018) Science — Vol. 359, n° 6383, p. 1464-1465 (2018)
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- Bacterial pathogens show a remarkable capacity to stick to host tissues and implanted biomaterials, grow, and form biofilms on these surfaces (1). These multicellular communities protect the bacteria from the host immune system and from drugs, thereby causing infections that are difficult to eradicate. Today, biofilms are estimated to be involved in half of all infections acquired in hospitals. On page 1527 of this issue, Milles et al. (2) combine single-molecule experiments and molecular dynamics simulations to study the forces involved in the adhesion of bacterial pathogens to host proteins, the first step of biofilm formation. Biofilm infections commonly involve Staphylococcus epidermidis and S. aureus strains, including methicillin-resistant S. aureus (MRSA). These microbes are decorated with adhesins that mediate both attachment to host proteins and cell-cell association (3). The structural features and molecular biology of staphylococcal adhesins have been widely investigated, but their binding forces are poorly understood because of a lack of ultrasensitive biophysical force probes. However, recent progress in single-molecule techniques (4) has provided new opportunities for studying forces in bacterial proteins (5). Unlike traditional methods that probe large ensembles of cells and molecules, atomic force microscopy (AFM) makes it possible to study bacterial components one molecule at a time (5). The technology has enabled researchers to understand the nanoscale biophysical properties of bacteria, unravel the binding mechanisms of their individual surface molecules, and decipher the forces guiding cell-cell and cell-substrate interactions (5). Milles et al. elegantly combine single-molecule AFM and steered molecular dynamics (SMD) simulations to investigate the molecular mechanism by which the prototypical staphylococcal adhesin SD-repeat protein G (SdrG) binds to fibrinogen (Fg), a host protein that rapidly coats implanted biomedical devices. They show that the extreme mechanical stability of the SdrG-Fg complex originates from an intricate hydrogen bond network between the ligand peptide backbone and the adhesin. The study represents an important step toward understanding how hospital-acquired pathogens use their surface adhesins to guide cell adhesion and trigger infections. SdrG binds to Fg via a dock, lock, and latch (DLL) mechanism that involves dynamic conformational changes of the protein, resulting in a greatly stabilized adhesin-ligand complex (6). The N2 and N3 subdomains of SdrG bind to a short peptide sequence in the Fg molecule (see the figure). Milles et al. used single-molecule AFM to quantify the mechanical strength of the SdrG-Fg complex. By immobilizing the SdrG subdomains on the AFM tip and the ligand peptides on a substrate, the authors could probe the forces between the interacting molecules in their native configuration. Consistent with earlier AFM experiments on living bacteria (7), these in vitro measurements revealed that the SdrG-Fg interaction is ultrastrong, with a strength of ∼2 nN, similar to that of covalent bonds (8).
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Herman-Bausier, P., & Dufrêne, Y. (2018). Force matters in hospital-acquired infections. Science, 359(6383), 1464-1465. https://doi.org/10.1126/science.aat3764 (Original work published 2018)