ORCID Profile
0000-0001-9081-4945
Current Organisation
University of Wrocław
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Publisher: Research Square Platform LLC
Date: 08-11-2022
DOI: 10.21203/RS.3.RS-2150762/V1
Abstract: Cell wall synthesis is an essential function for the growth of almost all bacteria, and a major target for our most effective antibiotics. Inhibition of cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. We have genetically dissected this connection in Bacillus subtilis and identified key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species (ROS) through cellular respiration. Our results also reveal the critical role of iron homeostasis for the ROS-mediated lethal effects, through iron-dependent enhancement of lipid peroxidation when cell wall synthesis is perturbed. Unexpectedly, we found that protection of cells from ROS via a recently discovered siderophore-like compound uncoupled changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be specifically associated with lipid peroxidation, presumably the result of membrane destabilization. Finally, we provide a new view of the differentiated roles of the widely conserved Rod and aPBP mechanisms of bacterial cell wall synthesis.
Publisher: American Chemical Society (ACS)
Date: 14-12-2020
DOI: 10.26434/CHEMRXIV.13286078.V1
Abstract: The application of genomic techniques to the investigation of understudied species of actinobacteria provides an expedited route to the discovery of new bioactive natural products. We report the isolation of the antibiotic polyketide tatiomicin, through a genomics and bioactivity informed analysis of the metabolome of the extremophile Amycolatopsis sp. DEM30355. Structural elucidation including absolute stereochemical assignment was performed using complementary crystallographic, spectroscopic and computational methods. Tatiomicin shows antibiotic activity against Gram-positive bacteria, including Methicillin-resistant Staphylococcus aureus (MRSA).
Publisher: Informa UK Limited
Date: 14-12-2016
DOI: 10.1080/14786419.2016.1263854
Abstract: The actinomycete DEM20745, collected from non-rhizosphere soil adjacent to Paraserianthes falactaria trees (Cangkringan, Indonesia), is an efficient producer of the anticancer ansamycin polyketide 17-O-demethyl-geldanamycin (17-O-DMG), a biosynthetic precursor of the Hsp90 inhibitor geldanamycin (GDM). In DEM20745, 17-O-DMG is the major ansamycin product observed reaching a maximum titre of 17 mg/L in the fermentation broth. 17-O-DMG has the potential to be a key starting material for the semi-synthesis of GDM analogues for use in anticancer therapy. Thus, this preferential biosynthesis of 17-O-DMG facilitates easy access to this important molecule and provides further insight in the biosynthesis of the geldanamycins.
Publisher: Cold Spring Harbor Laboratory
Date: 24-04-2022
DOI: 10.1101/2022.04.24.489322
Abstract: Growth of most rod-shaped bacteria is accompanied by the insertion of new peptidoglycan into the cylindrical cell wall. This insertion, which helps maintain and determine the shape of the cell, is guided by a complex protein machinery called the rod complex or elongasome. Although most of the proteins in this complex are essential under normal growth conditions, cell viability can be rescued, for reasons that are not understood, by the presence of a high (mM) Mg 2+ concentration. We screened for natural product compounds that could rescue the growth of mutants affected in rod-complex function. By screening ,000 extracts from a erse collection of actinobacteria, we identified a new compound, mirubactin B, related to the known iron siderophore mirubactin A, which rescued growth in the low micromolar range, and this activity was confirmed by synthesising mirubactin B. The compound also displayed toxicity at higher concentrations, and this effect appears related to iron homeostasis. However, several lines of evidence suggest that the mirubactin B rescuing activity is not due simply to iron sequestration. The results demonstrate a novel antibacterial compound and add to growing evidence that bacterial siderophores have a range of activities beyond simple iron sequestration.
Publisher: American Chemical Society (ACS)
Date: 14-12-2020
DOI: 10.26434/CHEMRXIV.13286078
Abstract: The application of genomic techniques to the investigation of understudied species of actinobacteria provides an expedited route to the discovery of new bioactive natural products. We report the isolation of the antibiotic polyketide tatiomicin, through a genomics and bioactivity informed analysis of the metabolome of the extremophile i Amycolatopsis /i sp. DEM30355. Structural elucidation including absolute stereochemical assignment was performed using complementary crystallographic, spectroscopic and computational methods. Tatiomicin shows antibiotic activity against Gram-positive bacteria, including Methicillin-resistant i Staphylococcus aureus /i (MRSA).
Publisher: Springer Science and Business Media LLC
Date: 11-07-2023
DOI: 10.1038/S41467-023-39723-8
Abstract: Inhibition of bacterial cell wall synthesis by antibiotics such as β-lactams is thought to cause explosive lysis through loss of cell wall integrity. However, recent studies on a wide range of bacteria have suggested that these antibiotics also perturb central carbon metabolism, contributing to death via oxidative damage. Here, we genetically dissect this connection in Bacillus subtilis perturbed for cell wall synthesis, and identify key enzymatic steps in upstream and downstream pathways that stimulate the generation of reactive oxygen species through cellular respiration. Our results also reveal the critical role of iron homeostasis for the oxidative damage-mediated lethal effects. We show that protection of cells from oxygen radicals via a recently discovered siderophore-like compound uncouples changes in cell morphology normally associated with cell death, from lysis as usually judged by a phase pale microscopic appearance. Phase paling appears to be closely associated with lipid peroxidation.
Publisher: Elsevier BV
Date: 10-2018
Publisher: American Chemical Society (ACS)
Date: 29-11-2017
DOI: 10.1021/ACSCHEMBIO.7B00733
Abstract: Antibiotics that interfere with the bacterial cytoplasmic membrane have long-term potential for the treatment of infectious diseases as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochemically complex polyketide chain. Vancoresmycin shows minimum inhibitory concentrations (MICs) from 0.125 to 2 μg/mL against a range of clinically relevant, antibiotic-resistant Gram-positive bacteria. Through a comprehensive mode-of-action study, utilizing Bacillus subtilis reporter strains, DiSC
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Bernhard Kepplinger.