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42 results on '"Kuipers, Oscar P"'

5. Brevibacillin 2V, a Novel Antimicrobial Lipopeptide With an Exceptionally Low Hemolytic Activity

Author

Zhao, Xinghong, Wang, Xiaoqi, Shukla, Rhythm, Kumar, Raj, Weingarth, Markus, Breukink, Eefjan, Kuipers, Oscar P, Sub Membrane Biochemistry & Biophysics, Sub NMR Spectroscopy, Membrane Biochemistry and Biophysics, NMR Spectroscopy, Molecular Genetics, Sub Membrane Biochemistry & Biophysics, Sub NMR Spectroscopy, Membrane Biochemistry and Biophysics, and NMR Spectroscopy

Subjects
Microbiology (medical), medicine.drug_class, Staphylococcus, Antibiotics, Microbiology, Enterococcus faecalis, 03 medical and health sciences, chemistry.chemical_compound, medicine, Original Research, 030304 developmental biology, 0303 health sciences, antimicrobial activity, biology, Brevibacillus, Chemistry, 030302 biochemistry & molecular biology, NRPS, Lipopeptide, brevibacillin, biology.organism_classification, Antimicrobial, QR1-502, Penicillin, Enterococcus, lipopeptide, Colistin, medicine.drug, Enterococcus faecium
Abstract

Bacterial non-ribosomally produced peptides (NRPs) form a rich source of antibiotics, including more than 20 of these antibiotics that are used in the clinic, such as penicillin G, colistin, vancomycin, and chloramphenicol. Here we report the identification, purification, and characterization of a novel NRP, i.e., brevibacillin 2V (lipo-tridecapeptide), from Brevibacillus laterosporus DSM 25. Brevibacillin 2V has a strong antimicrobial activity against Gram-positive bacterial pathogens (minimum inhibitory concentration = 2 mg/L), including difficult-to-treat antibiotic-resistant Enterococcus faecium, Enterococcus faecalis, and Staphylococcus aureus. Notably, brevibacillin 2V has a much lower hemolytic activity (HC50 > 128 mg/L) and cytotoxicity (CC50 = 45.49 ± 0.24 mg/L) to eukaryotic cells than previously reported NRPs of the lipo-tridecapeptide family, including other brevibacillins, which makes it a promising candidate for antibiotic development. In addition, our results demonstrate that brevibacillins display a synergistic action with established antibiotics against Gram-negative bacterial pathogens. Probably due to the presence of non-canonical amino acids and D-amino acids, brevibacillin 2V showed good stability in human plasma. Thus, we identified and characterized a novel and promising antimicrobial candidate (brevibacillin 2V) with low hemolytic activity and cytotoxicity, which can be used either on its own or as a template for further total synthesis and modification.

Published
2021
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42. CodY Regulates Thiol Peroxidase Expression as Part of the Pneumococcal Defense Mechanism against H 2 O 2 Stress.

Author

Hajaj B, Yesilkaya H, Shafeeq S, Zhi X, Benisty R, Tchalah S, Kuipers OP, and Porat N

Subjects
Bacterial Proteins genetics, Bacterial Proteins isolation & purification, Binding Sites, DNA, Bacterial genetics, Genes, Bacterial genetics, Host-Pathogen Interactions, Microorganisms, Genetically-Modified, Multigene Family, Oxidative Stress, Peroxidase genetics, Peroxidase isolation & purification, Point Mutation, Promoter Regions, Genetic, Protein Binding, Reactive Oxygen Species metabolism, Streptococcus pneumoniae genetics, Streptococcus pneumoniae growth & development, Sulfhydryl Compounds metabolism, Transcription Factors metabolism, Transformation, Genetic, Up-Regulation, Bacterial Proteins metabolism, Gene Expression Regulation, Bacterial, Hydrogen Peroxide metabolism, Peroxidase metabolism, Streptococcus pneumoniae enzymology, Streptococcus pneumoniae metabolism
Abstract

Streptococcus pneumoniae is a facultative anaerobic pathogen. Although it maintains fermentative metabolism, during aerobic growth pneumococci produce high levels of H 2 O 2 , which can have adverse effects on cell viability and DNA, and influence pneumococcal interaction with its host. The pneumococcus is unusual in its dealing with toxic reactive oxygen species (ROS) in that it neither has catalase nor the global regulators of peroxide stress resistance. Previously, we identified pneumococcal thiol peroxidase (TpxD) as the key enzyme for enzymatic removal of H 2 O 2 , and showed that TpxD synthesis is up-regulated upon exposure to H 2 O 2 . This study aimed to reveal the mechanism controlling TpxD expression under H 2 O 2 stress. We hypothesize that H 2 O 2 activates a transcription factor which in turn up-regulates tpxD expression. Microarray analysis revealed a pneumococcal global transcriptional response to H 2 O 2 . Mutation of tpxD abolished H 2 O 2 -mediated response to high H 2 O 2 levels, signifying the need for an active TpxD under oxidative stress conditions. Bioinformatic tools, applied to search for a transcription factor modulating tpxD expression, pointed toward CodY as a potential candidate. Indeed, a putative 15-bp consensus CodY binding site was found in the proximal region of tpxD- coding sequence. Binding of CodY to this site was confirmed by EMSA, and genetic engineering techniques demonstrated that this site is essential for TpxD up-regulation under H 2 O 2 stress. Furthermore, tpxD expression was reduced in a Δ codY mutant. These data indicate that CodY is an activator of tpxD expression, triggering its up-regulation under H 2 O 2 stress. In addition we show that H 2 O 2 specifically oxidizes the 2 CodY cysteines. This oxidation may trigger a conformational change in CodY, resulting in enhanced binding to DNA. A schematic model illustrating the contribution of TpxD and CodY to pneumococcal global transcriptional response to H 2 O 2 is proposed.

Published
2017
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