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Generic and specific adaptative response of S. pneumoniae to challenge with three distinct antimicrobial peptides

ABSTRACT: To investigate the response of S. pneumoniae to three distinct antimicrobial peptides (AMPs), i.e. bacitracin, nisin and LL-37, transcriptome analysis of challenged bacteria was performed. Only a limited number of genes was found to be up- or down-regulated in all cases. Several of these common highly induced genes were chosen for further analysis, i.e. SP0385-0387, SP0912-0913, SP0785-0787, SP1714-1715 and the blp cluster. Deletion of these genes in combination with MIC determinations showed that several putative transporters, i.e. SP0785-0787 and SP0912-0913, were indeed involved in resistance to lincomycin, LL-37 and to bacitracin, nisin, lincomycin, respectively. Mutation of blp-bacteriocin production and its immunity genes resulted in an increased of sensitivity to LL-37. Interestingly, a putative ABC transporter (SP1715) protected against bacitracin and Hoechst 33342, but confered sensitivity to LL-37. A GntR-like regulator, SP1714, was identified as a negative regulator of itself and two of the putative transporters. In conclusion, we show that resistance to three different AMPs in S. pneumoniae is mediated by several putative ABC transporters, some of which have not been associated with antimicrobial resistance in this organism before. In addition, a GntR-like regulator was identified, which regulates two of these transporters. Our findings extend the undertstanding of defense mechanisms of this important human pathogen against antimicrobial compounds and points toward novel proteins, i.e. putative ABC transporters, which can be used as targets for the development of new antimicrobials.

ORGANISM(S): Streptococcus pneumoniae D39 Streptococcus pneumoniae

PROVIDER: GSE16491 | GEO | 2010/01/08

SECONDARY ACCESSION(S): PRJNA116009

REPOSITORIES: GEO

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Project description:Understanding how pathogens respond to antimicrobial peptides, and how this compares to currently available antibiotics, is crucial to optimizing antibiotic therapy. Staphylococcus aureus has several known resistance mechanisms against human cationic antimicrobial peptides (CAMPs). We aim to determine how S. aureus responds to sheep and frog CAMPs, and whether this response is associated with resistance. Gene expression changes in Staphylococcus aureus Newman cells exposed to linear CAMPs were analyzed by DNA microarray. Three antimicrobial peptides were used in the analysis, two of them are derived from frog, temporin L and dermaseptin K4-S4(1-16), one is from sheep, ovispirin-1. The peptides induced the VraSR cell-wall regulon and several other genes which are also upregulated in cells treated with vancomycin and other cell wall-active antibiotics. In addition to this similarity, three genes/operons were particularly strongly induced by the peptides: vraDE, SA0205 and SAS016, encoding an ABC transporter, a putative membrane-bound lysostaphin-like peptidase and a small functionally unknown protein, respectively. Ovispirin-1 and dermaseptin K4-S4(1-16), which disrupt lipid bilayers by the carpet mechanism, were strong inducers of the vraDE operon. We show that high level induction by ovispirin-1 was dependent on the amide modification of the peptide C-terminus. This suggests that the amide group has a crucial role in the activation of the Aps sensory system, the regulator of vraDE. In contrast, temporin L, which disrupts lipid bilayers by forming pores, was clearly a weaker inducer of vraDE despite the C-terminal amide modification. Sensitivity testing with CAMPs and other antimicrobials suggested that VraDE is a transporter dedicated to resist bacitracin. We also showed that SA0205 belongs to the VraSR regulon. Furthermore, VraSR was shown to be important for resistance against a wide range of cell wall-active antibiotics and other antimicrobial agents including the amide-modified ovispirin-1, bacitracin, teicoplanin, cefotaxime and 10 other β-lactam antibiotics, chlorpromazine, thioridazine and EGTA. The effects of the three different antimicrobial peptides on gene expression of S. aureus Newman were studied by using whole genome oligo-DNA microarrays. Bacteria were grown in BHI medium to the early exponential phase (OD600=0.6) and antimicrobial peptides were added at sublethal concentrations. Samples were taken for RNA isolations after treating the cultures with the peptides for 10 minutes. Control cultures without peptide additions were treated similarly and in parallel.

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Generic and specific adaptative response of S. pneumoniae to challenge with three distinct antimicrobial peptides

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