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.

Keywords: Antivirulence; Arylomycin; Protein translocation; SPase; Secretion.

Figure 1

Cleavage of the signal peptide (shown in cyan) from the encoded pre-protein completes secretion across the cytoplasmic membrane. Components shown are the (1) unfolded pre-protein, (2) SPase, (3) Sec translocon, (4) translocated pre-protein, and (5) secreted mature protein.

Figure 2

Gram-negative SPase-dependent secretion systems: type II (blue), Type V (substrate’s β-barrel domain is shown in red before and after insertion into the OM), type VIII (purple) chaperone/usher (yellow). The Sec translocon and SPase are shown in green and light purple, respectively. Signal peptides are shown in cyan. OM: outer membrane; CM: cytoplasmic membrane

Figure 3

Sec-independent secretion systems. Components of the secretion machinery that require SPase for processing are highhlighted in yellow and labeled. Grey components lack identifiable type I signal peptides. VirB9 forms a complex with VirB7 (not labeled). The T6SS is the only identified system without a component that depends on SPase. Detailed discussion of the structure and biogenesis of these secretion systems can be found elsewhere.^,– HM: host membrane; OM: outer membrane; CM: cytoplasmic membrane.

Figure 4

Canonical (left) and non-canonical (right) signal peptides (cyan). Cleavage sites are indicated with an arrow.