Not just an antibiotic target: Exploring the role of type I signal peptidase in bacterial virulence

Abstract

The looming antibiotic crisis has prompted the development of new strategies towards fighting infection. Traditional antibiotics target bacterial processes essential for viability, whereas proposed antivirulence approaches rely on the inhibition of factors that are required only for the initiation and propagation of infection within a host. Although antivirulence compounds have yet to prove their efficacy in the clinic, bacterial signal peptidase I (SPase) represents an attractive target in that SPase inhibitors exhibit broad-spectrum antibiotic activity, but even at sub-MIC doses also impair the secretion of essential virulence factors. The potential consequences of SPase inhibition on bacterial virulence have not been thoroughly examined, and are explored within this review. In addition, we review growing evidence that SPase has relevant biological functions outside of mediating secretion, and discuss how the inhibition of these functions may be clinically significant.

Repurposing human kinase inhibitors to create an antibiotic active against drug-resistant Staphylococcus aureus, persisters and biofilms

“…While inhibition of SpsB with arylomycin, which is believed to cause cell death by accumulation of unprocessed proteins, has been studied by proteomic analysis of the bacterial secretome, [32][33][34] little is known about the underlying stimulating effects. In order to understand how activation of SpsB affects the secretome, we analysed extracellular proteins in the presence of SFN and PK150 as well as in the presence of inactive SFN-C and PK150-C (Table 2, Fig.…”

Involvement of signal peptidase I in Streptococcus sanguinis biofilm formation

“…The signal peptide sequence, a ‘zipcode’ that guides the preproteins to the Sec or Tat membrane-embedded pore (translocon), is cleaved by SPase during or shortly after translocation, releasing the translocated protein from the membrane and allowing its folding into a mature protein. SPases represent an attractive target for drug development for many reasons: they are ubiquitous [ 16 ]; often essential [ 17 ]; accessible to drugs as their active sites are exposed to the extracellular region [ 18, 19 ]. Bacterial species such as E. coli have only one essential SPase enzyme, while most Gram-positive bacteria have multiple enzymes [ 15, 20–22 ].…”

Inhibition of Protein Secretion in Escherichia coli and Sub-MIC Effects of Arylomycin Antibiotics

“…Clearly the transfer of DNA per se does not require SPase activity, and the inhibition of HGT likely results from the inhibited assembly of the required T4SS, which possesses multiple components that are predicted to rely on SPase for localization (54). Similarly, components of nearly all specialized secretion systems rely on SPase for proper localization (39) and thus, the inhibition of their functions is likely to be included in the activity of an arylomycin therapeutic.…”

“…1), and they are currently under development in the pharmaceutical industry as broad-spectrum therapeutics (35)(36)(37). While the mechanism of arylomycin killing is the accumulation of unprocessed preproteins in the cytoplasmic membrane, which compromises the membrane's integrity (38), the inhibition of SPase obviously also prevents the proper localization of extracytoplasmic proteins, and, as a result, sub-MIC levels of an arylomycin could in theory reduce virulence and possibly other processes that rely on extracytoplasmic proteins (39).…”