Signal Peptidase-Mediated Cleavage of the Anti-σ Factor RsiP at Site 1 Controls σ ^P Activation and β-Lactam Resistance in Bacillus thuringiensis

Abstract

β-Lactam antibiotics are important for the treatment of many bacterial infections. However, resistance mechanisms have become increasingly more prevalent.

The role of site-2-proteases in bacteria: a review on physiology, virulence, and therapeutic potential

“…Upon activation, σ P regulates expression of multiple β-lactamases and penicillin binding proteins (PBP) (Ho et al 2022 ), providing B. thuringiensis with an arsenal of protection strategies. The activity of σ P is hindered by the anti-sigma factor RsiP, which, in response to selected β-lactams, is successively cleaved by the S1P SipP and the S2P RasP (Ho et al 2019 , Nauta et al 2022 ). It is suggested that penicillin-binding protein P (PbpP) acts as a sensor for β-lactams, somehow activating the S1P cleavage of the RIP cascade (Nauta et al 2021 ).…”

“…It is suggested that penicillin-binding protein P (PbpP) acts as a sensor for β-lactams, somehow activating the S1P cleavage of the RIP cascade (Nauta et al 2021 ). Δ pbpP , Δ sipP , and Δ rasP increase susceptibility to ampicillin and cefoxitin (Ho et al 2019 , Nauta et al 2021 , Nauta et al 2022 ), underpinning the RIP cascade's role in σ P mediated β-lactam resistance. Similar cascades is observed in B. subtilis , where σ W participates in response to a variety of cell wall inhibiting antibiotics and antimicrobial peptides (Cao et al 2002 , Pietiäinen et al 2005 , Butcher and Helmann 2006 ).…”

“…In contrast, B. thuringiensis σ P is activated only by a specific subset of β-lactams, not other cell wall-targeting antibiotics, suggesting that σ P is not activated in response to general cell wall stress (Ho et al 2019 ). It should be noted that σ P also has been linked to resistance against β-lactams in Bacillus cereus and Bacillus anthracis (Ross et al 2009 , Nauta et al 2022 ). RasP is conserved in these closely related human pathogens, suggesting a role of RIP-mediated antibiotic resistance in these species.…”