Contributions of the σ^W, σ^M and σ^X regulons to the lantibiotic resistome of Bacillus subtilis

Abstract

Summary In Bacillus subtilis, the extracytoplasmic function (ECF) σ factors σM, σW, and σX all contribute to resistance against lantibiotics. Nisin, a model lantibiotic, has a dual mode of action: it inhibits cell wall synthesis by binding lipid II, and this complex also forms pores in the cytoplasmic membrane. These activities can be separated in a nisin hinge-region variant (N20P M21P) that binds lipid II, but no longer permeabilizes membranes. The major contribution of σM to nisin resistance is expression of ltaSa, encoding a stress-activated lipoteichoic acid synthase, and σX functions primarily by activation of the dlt operon controlling D-alanylation of teichoic acids. Together, σM and σX regulate cell envelope structure to decrease access of nisin to its lipid II target. In contrast, σW is principally involved in protection against membrane permeabilization as it provides little protection against the nisin hinge region variant. σW contributes to nisin resistance by regulation of a signal peptide peptidase (SppA), phage shock proteins (PspA and YvlC, a PspC homolog), and tellurite resistance related proteins (YceGHI). These defensive mechanisms are also effective against other lantibiotics such as mersacidin, gallidermin, and subtilin and comprise an important subset of the intrinsic antibiotic resistome of B. subtilis.

Protecting from Envelope Stress: Variations on the Phage-Shock-Protein Theme

“…Interestingly, YvlC is an ortholog of E. coli PspC, but with about half the length and only ~30% amino acid sequence identity. The effects of inactivating pspA and yvlC on nisin resistance are additive, indicating that the two functions are independent, at least in part [40]. This result is consistent with PspA and PspC having independent effector functions in Gram-negative bacteria, as described above.…”

“…The gene annotated as pspA is regulated by the accessory sigma factor σ W , which directs transcription to genes involved in protecting the cell membrane from permeabilization by lantibiotics (antimicrobial peptides that are produced by Gram-positive bacteria [39]). The σ W regulon includes sppA, which encodes a signal-peptide peptidase hypothesized to degrade lantibiotics, and the operons yceCDEFGHI and yvlABCD [40]. While the functions of these operons are largely unknown, two proteins, YceH and YvlC, lower susceptibility to the lantibiotic nisin.…”

“…Following stress-mediated induction of the operon, the concentration of these two proteins increases, and LiaI recruits LiaH to numerous static foci on the cytoplasmic side of the cell membrane [10]. The role of LiaIH in the response to membranedamaging antibiotics suggests that these proteins contribute to preserving membrane integrity, as is the case with the Psp response of Gram-negative bacteria [40,44]. Whether LiaH also exerts regulatory functions is unclear.…”

Cannibalism stress response in Bacillus subtilis

“…Whilst the BceRS and PsdRS systems regulate ATP-binding cassette (ABC) transporters (BceAB and PsdAB, respectively) that specifically confer resistance against a number of AMPs (Staroń et al, 2011), the regulons of the ECF s factors are known to play a more promiscuous role in CESR to antimicrobial compounds (Helmann, 2002;Kingston et al, 2013;Mascher et al, 2007;Missiakas & Raina, 1998). s M , s X and s W each regulate a set of *30-60 target genes with partially overlapping specificity (Kingston et al, 2013;Mascher et al, 2007), and all are activated in a growth-phase-and growth-mediumdependent manner (Huang et al, 1998). Whilst s M and s X are induced mainly in the late exponential growth phase, s W only becomes active in the early stationary phase (Huang et al, 1998;Nicolas et al, 2012).…”

Regulation of bacterial virulence gene expression by cell envelope stress responses

“…They include at least 4 ECF s factors in B. subtilis (s M , s W , s X and s V ) that respond to antibiotics and CAMPs to control numerous target genes. [136][137][138][139][140] However, relatively little is known about ECF s factors in other Gram-positive bacteria. Other members of this category include 2 component regulatory systems.…”