FIGURE 2: Model for alternative secretion compensating for the lack of type I signal peptidase SpsB activity in S. aureus.

(A) The most common route for proteins destined for secretion involves translocation across the S. aureus cell membrane through the general secretory (Sec) translocon, and subsequent cleavage by SpsB of the signal (or leader) peptide allowing release from the membrane. SpsB also cleaves the N-terminal signal peptides of proteins secreted through the Tat protein export system.

(B) When SpsB is inhibited, these proteins are not cleaved and hence not secreted, causing accumulation of unprocessed proteins, and eventually resulting in cell death.

(C) Over-expression of the putative ABC transporter (as in S. aureus with mutations in the transcriptional repressor cro/cI) compensates for a lack of SpsB activity. This transporter mediates SpsB-independent cleavage of a subset of proteins at an alternative cleavage site, leading to their secretion. This alternative secretion pathway is able to restore viability under conditions of either pharmacological SpsB inhibition (in which case it constitutes the main resistance mechanism) or genetic disruption of SpsB expression. For more details see reference [3].

3. Morisaki JH, Smith PA, Date SV, Kajihara KK, Truong CL, Modrusan Z, Yan D, Kang J, Xu M, Shah IM, Mintzer R, Kofoed EM, Cheung TK, Arnott D, Koehler MFT, Heise CE, Brown EJ, Tan MW, Hazenbos WLW (2016). A putative bacterial ABC transporter circumvents the essentiality of signal peptidase. mBio 7(5): e00412-16. https://doi.org/10.1128/mBio.00412-16