msaABCR operon positively regulates biofilm development by repressing proteases and autolysis in Staphylococcus aureus

Abstract

Staphylococcus aureus is an important human pathogen that causes nosocomial and community-acquired infections. One of the most important aspects of staphylococcal infections is biofilm development within the host, which renders the bacterium resistant to the host’s immune response and antimicrobial agents. Biofilm development is very complex and involves several regulators that ensure cell survival on surfaces within the extracellular polymeric matrix. Previously, we identified the msaABCR operon as an additional positive regulator of biofilm formation. In this study, we define the regulatory pathway by which msaABCR controls biofilm formation. We demonstrate that the msaABCR operon is a negative regulator of proteases. The control of protease production mediates the processing of the major autolysin, Atl, and thus regulates the rate of autolysis. In the absence of the msaABCR operon, Atl is processed by proteases at a high rate, leading to increased cell death and a defect in biofilm maturation. We conclude that the msaABCR operon plays a key role in maintaining the balance between autolysis and growth within the staphylococcal biofilm.

MsaB activates capsule production at the transcription level in Staphylococcus aureus

“…Previously, we have shown that the msaABCR operon is involved in virulence, biofilm development and antibiotic resistance (Sambanthamoorthy et al, 2006(Sambanthamoorthy et al, , 2008Sahukhal & Elasri, 2014;Samanta & Elasri, 2014;Sahukhal et al, 2015). In this study, we found that MsaB, encoded by the msaABCR operon, binds directly to a previously identified 10 bp inverted regulatory repeat located immediately upstream from the identified cap promoter region.…”

“…However, given the pleiotropic effect of deletion of the msaABCR operon, we cannot rule out factors other than the lack of capsule production in the reduced survival of the msaABCR mutant. Indeed, we have also shown in several of our studies that the msaABCR operon plays a role in regulation of many virulence factors, biofilm development and antibiotic resistance (Sambanthamoorthy et al, 2006(Sambanthamoorthy et al, , 2008Samanta & Elasri, 2014;Sahukhal & Elasri, 2014;Sahukhal et al, 2015). Further studies are needed to examine the putative contribution of other factors affected by the msaABCR operon.…”

“…We previously identified the msaABCR operon, which is involved in the regulation of virulence, biofilm development and antibiotic resistance in S. aureus (Sambanthamoorthy et al, 2006(Sambanthamoorthy et al, , 2008Samanta & Elasri, 2014;Sahukhal & Elasri, 2014;Sahukhal et al, 2015). The deletion of the msaABCR operon alters the expression of several global regulators, including sarA, agr and sigB, all of which have been shown to be indirectly involved in capsule production (Bischoff et al, 2004;Pané-Farré et al, 2006;Meier et al, 2007;Dassy et al, 1993;Sahukhal & Elasri, 2014).…”

Role of the msaABCR Operon in Cell Wall Biosynthesis, Autolysis, Integrity, and Antibiotic Resistance in Staphylococcus aureus

“…We have also shown that msaABCR mutants are defective in persister cell formation under cell wall-targeting antibiotic (vancomycin and daptomycin) stress conditions in the USA300 LAC strain background (26). Increases in Triton X-100-induced autolysis and protease production are also major phenotypes of the msaABCR-deletion mutant (21,22). We previously showed that the msaABCR operon represses protease activity regulating the expression of four extracellular proteases (Aur, Scp, Ssp, and Spl) in various growth phases, including the early exponential growth phase (21,23).…”

“…These reports have rekindled interest in targeting genes involved in the maintenance of cell wall integrity and ultimately resensitizing resistant strains (4,7,(13)(14)(15)(16)(17)(18)(19)(20). Previously, we showed that the msaABCR operon plays a role in biofilm development, virulence, persister cell formation, and antibiotic resistance in S. aureus (21)(22)(23)(24)(25)(26). The msaABCR operon is a four-gene operon composed of msaA, msaB, msaC, and an antisense RNA, msaR (23).…”