The lantibiotic mersacidin is a strong inducer of the cell wall stress response of Staphylococcus aureus

Abstract

BackgroundThe lantibiotic mersacidin is an antimicrobial peptide of 20 amino acids that is ribosomally produced by Bacillus sp. strain HIL Y-85,54728. Mersacidin acts by complexing the sugar phosphate head group of the peptidoglycan precursor lipid II, thereby inhibiting the transglycosylation reaction of peptidoglycan biosynthesis.ResultsHere, we studied the growth of Staphylococcus aureus in the presence of subinhibitory concentrations of mersacidin. Transcriptional data revealed an extensive induction of the cell wall stress response, which is partly controlled by the two-component regulatory system VraSR. In contrast to other cell wall-active antibiotics such as vancomycin, very low concentrations of mersacidin (0.15 × MIC) were sufficient for induction. Interestingly, the cell wall stress response was equally induced in vancomycin intermediately resistant S. aureus (VISA) and in a highly susceptible strain. Since the transcription of the VraDE ABC transporter genes was induced up to 1700-fold in our experiments, we analyzed the role of VraDE in the response to mersacidin. However, the deletion of the vraE gene did not result in an increased susceptibility to mersacidin compared to the wild type strain. Moreover, the efficacy of mersacidin was not affected by an increased cell wall thickness, which is part of the VISA-type resistance mechanism and functions by trapping the vancomycin molecules in the cell wall before they reach lipid II. Therefore, the relatively higher concentration of mersacidin at the membrane might explain why mersacidin is such a strong inducer of VraSR compared to vancomycin.ConclusionIn conclusion, mersacidin appears to be a strong inducer of the cell wall stress response of S. aureus at very low concentrations, which reflects its general mode of action as a cell wall-active peptide as well as its use of a unique target site on lipid II. Additionally, mersacidin does not seem to be a substrate for the resistance transporter VraDE.

Lantibiotic Resistance

“…In other words, resistance is dependent on attack in the form of inhibition of cell wall synthesis, which in turn activates the VraS sensor kinase. In addition, VraSR is independently activated upon inhibition of cell wall biosynthesis, such as that observed through the action of mersacidin, daptomycin, and vancomycin (124,155). However, a study by Muthaiyan et al revealed that unlike daptomcin and vancomycin in the previous study, nisin treatment did not induce vraSR expression (156).…”

“…Although mersacidin also has the same target molecule, it does not bind to the D-alanyl-D-alanine terminus. Resistance to mersacidin is not hindered in such a manner but is still observed to induce the VraSR TCS (130,155,158). However, a recent study by Berscheid et al identified two mutations in VraS (L114S and D242G) which contribute to an enhanced thickening of the cell wall and lead to increased resistance to mersacidin (159).…”

Further Insights into the Mode of Action of the Lipoglycopeptide Telavancin through Global Gene Expression Studies

“…To this list we can add telavancin and enduracidin as strong inducers. Sass et al (43,44) have pointed out that strong inducers of vraDE disrupt bilayers by the carpet mechanism. Interestingly, vraD and vraE were not induced by CCCP, which is probably a pure uncoupling agent interacting with the membrane in a different way than the compounds above.…”

“…vraD and vraE were induced strongly by telavancin (84-and 82-fold, respectively) and enduracidin (42.6-and 32.4-fold), and more weakly (not significantly and 16.1-fold) by vancomycin (Table 3). VraDE comprise an ABC transporter involved in antimicrobial peptide detoxification (40,43). The system is induced by various antimicrobial peptides, including bacitracin, nisin, mersacidin, indolicidin, ovisporin-1-NH 2 , temporin-1-NH 2 , dermaseptin, K4-S4 (1-16)-NH 2 , vancomycin, and teicoplanin (13,16,27,40,43,53).…”

“…Both transcriptomic and proteomic studies have been reported over the past 10 years, and the findings were drawn together in reviews by Wecke and Mascher (50) and Wenzel and Bandow (51) in 2011. Cell wall-active antibiotics typically induce what is termed the cell wall stress stimulon or cell envelope stress response in Gram-positive bacteria (19,24,43,48). A key two-component system controlling part of the cell wall stress stimulon is VraSR in S. aureus, or its homolog LiaSR in Bacillus subtilis.…”