Dataset Information

Mechanism of BceAB-type transporter: Resistance by lipid II flipping

ABSTRACT: Treatment of bacterial infections are the great challenge of our era due to the evolved resistance mechanisms against antibiotics. The Achilles heel of bacteria is the cell wall especially during the needs of its synthesis and cell division. Here lipid II is an essential precursor component synthesized in the cytosol and flipped into the outer leaflet of the membrane prior to application into the cell wall. Compounds targeting the cell wall or its biosynthesis precursors have been around for decades and have been used as antibiotics against bacterial infections like meningitis, pneumonia and endocarditis. In the last decades however resistance against those antibiotics evolved and antimicrobial peptides (AMPs) have been found to be promising alternative antibiotics. The Bacitracin efflux (BceAB)-type ATP binding cassette transporters expressed in the membrane of human pathogenic bacteria confer resistance against these alternative antibiotics and thereby their medical development is hampered. Here we elucidated the mechanism of the BceAB-type transporter NsrFP from Streptococcus agalactiae COH1 (SaNsrFP), described to confer high resistance against the antimicrobial peptide nisin, a member of the lantibiotic subfamily. We showed that SaNsrFP is using a novel mechanism of resistance by flipping lipid II back into the cytosol thereby preventing the binding of nisin as well as other lipid II targeting compounds. This trick is intriguing since it uses a relative simple mechanism resulting in the resistance of the human pathogenic bacteria against a structurally divers group of potent antibiotics.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Lactococcus Lactis Subsp. Cremoris Nz9000 Bacteria

SUBMITTER: Nina Overbeck

LAB HEAD: Kai Stühler

PROVIDER: PXD017318 | Pride | 2022-04-04

REPOSITORIES: Pride

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Publications

New insights into the resistance mechanism for the BceAB-type transporter SaNsrFP.

Gottstein Julia J Zaschke-Kriesche Julia J Unsleber Sandra S Voitsekhovskaia Irina I Kulik Andreas A Behrmann Lara V LV Overbeck Nina N Stühler Kai K Stegmann Evi E Smits Sander H J SHJ

Scientific reports 20220310 1

Treatment of bacterial infections is one of the major challenges of our time due to the evolved resistance mechanisms of pathogens against antibiotics. To circumvent this problem, it is necessary to understand the mode of action of the drug and the mechanism of resistance of the pathogen. One of the most potent antibiotic targets is peptidoglycan (PGN) biosynthesis, as this is an exclusively occurring and critical feature of bacteria. Lipid II is an essential PGN precursor synthesized in the cyt ...[more]

PMID: 35273305

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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.

Dataset Information

Mechanism of BceAB-type transporter: Resistance by lipid II flipping

Publications

New insights into the resistance mechanism for the BceAB-type transporter SaNsrFP.

Similar Datasets

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