Staphylococcus aureus type I signal peptidase: essential or not essential, that’s the question

Abstract

Secretion of proteins into the extracellular environment is crucial for the normal physiology and virulence of pathogenic bacteria. Type I signal peptidase (SPase I) mediates the final step of bacterial secretion, by cleaving proteins at their signal peptide once they are translocated by the Sec or twin-arginine (Tat) translocon. SPase I has long been thought to be essential for viability in multiple bacterial pathogens. Challenging this view, we and others have recently created Staphylococcus aureus bacteria lacking the SPase I SpsB that are viable and able to grow in vitro when over-expressing a native gene cassette encoding for a putative ABC transporter. This transporter apparently compensates for SpsB's essential function by mediating alternative cleavage of a subset of proteins at a site distinct from the SpsB-cleavage site, leading to SpsB-independent secretion. This alternative secretion system also drives the main mechanism of resistance to an arylomycin-derived SpsB inhibitor, by means of mutations in a putative transcriptional repressor (cro/cI) causing over-expression of the ABC transporter. These findings raise multiple interesting biological questions. Unraveling the mechanism of SpsB-independent secretion may provide an interesting twist to the paradigm of bacterial secretion.

Role of Maturation of Lipoproteins in the Pathogenesis of the Infection Caused by Streptococcus suis Serotype 2

“…The Lgt enzyme contributes to virulence of S. pneumoniae [21] and S. aureus [51] in mouse infection models. The Lsp enzyme is required for the full virulence of L. monocytogenes [60], Mycobacterium tuberculosis [13] and S. aureus [61]. In the current study, and using a mouse model of systemic infection, it was shown that the Lgt and Lsp enzymes influence the virulence of the highly virulent S. suis serotype 2 ST7 strain SC84.…”

Secondary Metabolites Governing Microbiome Interaction of Staphylococcal Pathogens and Commensals

“…The gene agrD encodes a precursor peptide consisting of a core peptide that is flanked by an N-terminal amphipathic helical region and a C-terminal highly negatively charged recognition sequence [Thoendel and Horswill, 2009]. AgrD is processed by AgrB, a membrane protein with endopeptidase activity, and an additional protease that is thought to be SpsB, the general signal peptidase associated with Sec and Tat secretion system [Hazenbos et al, 2017), via the following (proposed) pathway [Thoendel and Horswill, 2009]: Upon translation, the precursor peptide localizes to the inner leaflet of the cell membrane via the N-terminal amphipathic helix structure [Zhang et al, 2004]. In the next step, AgrB removes the C-terminal recognition sequence of the precursor peptide, which is followed by formation of the thiolactone ring between a Cys of the core peptide and its C-terminus [Thoendel and Horswill, 2009].…”

Instructive Advances in Chemical Microbiology Inspired by Nature’s Diverse Inventory of Molecules

“…■ ARYLOMYCINS: NEW GRAM-NEGATIVE ANTIBIOTICS THAT TARGET LepB Arylomycin antibiotics are macrocyclic lipopeptides that inhibit bacterial type I signal peptidase (SPase), 63,64 an essential membrane-bound protease that cleaves signal sequences from preproteins following their translocation across the cytoplasmic membrane utilizing a serine-lysine dyad 65,66 (e.g., arylomycin A-C 16 12, Figure 4). There is considerable interest in advancing arylomycin antibiotics and related analogues for therapeutic applications.…”