agr-Mediated Dispersal of Staphylococcus aureus Biofilms

By Blaise R. Boles, A. Horswill. PLoS Pathogens, 2008

935 citations recorded by the source corpus.

The agr quorum-sensing system of Staphylococcus aureus modulates the expression of virulence factors in response to autoinducing peptides (AIPs). Recent studies have suggested a role for the agr system in S. aureus biofilm development, as agr mutants exhibit a high propensity to form biofilms, and cells dispersing from a biofilm have been observed displaying an active agr system. Here, we report that repression of agr is necessary to form a biofilm and that reactivation of agr in established biofilms through AIP addition or glucose depletion triggers detachment. Inhibitory AIP molecules did not induce detachment and an agr mutant was non-responsive, indicating a dependence on a functional, active agr system for dispersal. Biofilm detachment occurred in multiple S. aureus strains possessing divergent agr systems, suggesting it is a general S. aureus phenomenon. Importantly, detachment also restored sensitivity of the dispersed cells to the antibiotic rifampicin. Proteinase K inhibited biofilm formation and dispersed established biofilms, suggesting agr-mediated detachment occurred in an ica-independent manner. Consistent with a protease-mediated mechanism, increased levels of serine proteases were detected in detaching biofilm effluents, and the serine protease inhibitor PMSF reduced the degree of agr-mediated detachment. Through genetic analysis, a double mutant in the agr-regulated Aur metalloprotease and the SplABCDEF serine proteases displayed minimal extracellular protease activity, improved biofilm formation, and a strongly attenuated detachment phenotype. These findings indicate that induction of the agr system in established S. aureus biofilms detaches cells and demonstrate that the dispersal mechanism requires extracellular protease activity.

Subfields: Infectious Diseases, Microbiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eae8b33836d247676262c8c3f6da3695ab43a55b

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Citations in the corpus

Bacterial quorum sensing: its role in virulence and possibilities for its control. (2012, background): “One interpretation of this finding is that establishing a biofilm community at LCD allows S. aureus time to grow to HCD and, at that point, it is optimally poised to secrete virulence factors (Yarwood et al. 2004; Boles and Horswill 2008).”
Quorum sensing in staphylococci. (2008, background): “Kavanaugh JS, Thoendel M, Horswill AR. 2007.”
Nasal carriage as a source of agr-defective Staphylococcus aureus bacteremia. (2012, background): “However, agr-defective mutants are frequently isolated from clinical material and laboratory cultures [3, 10, 20, 21, 24, 25].”
Signals, Regulatory Networks, and Materials That Build and Break Bacterial Biofilms (2009, background): “dependent on production of extracellular proteases, including the agr-regulated Aur metalloprotease and the splABCDEF encoded serine proteases (31).”
How Staphylococcus aureus biofilms develop their characteristic structure (2012, background): “aureus (7, 8); however, how such enzymes contribute to biofilm maturation awaits in-depth investigation.”
Coagulase-Negative Staphylococci (2014, background): “Increased biofilm formation could also be explained by a decreased detachment rate, as thicker biofilms of the agr mutant may result from a lack of upregulation of different genes involved in biofilm detachment, such as proteases, nucleases, and PSMs, by agr (318, 362, 376).”
Healthcare-associated infections, medical devices and biofilms: risk, tolerance and control. (2015, background): “In the case of S. aureus, not only has the repression of the agrrelated QS regulatory gene been shown to play a role in biofilm formation, but its activation has also been reported to induce the release of S. aureus cells from the biofilm (Boles & Horswill, 2008).”
Biofilm Dispersal: Mechanisms, Clinical Implications, and Potential Therapeutic Uses (2010, background): “Exogenous autoinducing peptide AIP-I induces sloughing of S. aureus biofilms cultured in flow cells (Boles and Horswill, 2008; Lauderdale et al., 2009).”
Biofilm formation in Staphylococcus implant infections. A review of molecular mechanisms and implications for biofilm-resistant materials. (2012, background): “cells or cell clusters by various mechanisms, is crucial for the dissemination of the bacteria to new infection sites in the human body [102,103].”
Bacterial Extracellular Polysaccharides in Biofilm Formation and Function (2015, background): “However, staphylococcal strains demonstrate a wide range of bio ﬁ lm phenotypes, and many strains maintain the ability to form bio ﬁ lms in the absence of PIA (32, 47, 48), where several PIA-independent protein factors and/or eDNA seem to be more important (8, 49, 50).”
Strategies for combating bacterial biofilms: A focus on anti-biofilm agents and their mechanisms of action (2017, background): “agr system prevents biofilm maturation, performing an inhibitory role.(29) The production of extracellular proteases (eg.”
Staphylococcal biofilms (2018, background): “epidermidis (75, 91), and applying the extracellular autoinducing peptide (AIP) signal of the Agr quorum-sensing system results in biofilm dispersal (79).”