Publications of the research group Chemical Biology (CBIO)http://hdl.handle.net/10033/6205342024-03-29T05:26:33Z2024-03-29T05:26:33ZNew Frontiers in Drug Discovery: Academia Meets Industry at the International Helmholtz Drug Discovery Conference (HDDC).Göttlicher, MartinSattler, MichaelBrönstrup, Markhttp://hdl.handle.net/10033/6232182022-06-14T01:55:44Z2020-02-21T00:00:00ZNew Frontiers in Drug Discovery: Academia Meets Industry at the International Helmholtz Drug Discovery Conference (HDDC).
Göttlicher, Martin; Sattler, Michael; Brönstrup, Mark
2020-02-21T00:00:00ZInhibition of Type IV Secretion Activity and Growth of by Cisplatin and Other Platinum Complexes.Lettl, ClaraSchindele, FranziskaTestolin, GiambattistaBär, AlexanderRehm, TobiasBrönstrup, MarkSchobert, RainerBilitewski, UrsulaHaas, RainerFischer, Wolfganghttp://hdl.handle.net/10033/6232082022-06-14T01:54:59Z2020-12-18T00:00:00ZInhibition of Type IV Secretion Activity and Growth of by Cisplatin and Other Platinum Complexes.
Lettl, Clara; Schindele, Franziska; Testolin, Giambattista; Bär, Alexander; Rehm, Tobias; Brönstrup, Mark; Schobert, Rainer; Bilitewski, Ursula; Haas, Rainer; Fischer, Wolfgang
Type IV secretion systems are protein secretion machineries that are frequently used by pathogenic bacteria to inject their virulence factors into target cells of their respective hosts. In the case of the human gastric pathogen Helicobacter pylori, the cytotoxin-associated gene (Cag) type IV secretion system is considered a major cause for severe disease, such as gastric cancer, and thus constitutes an attractive target for specific treatment options against H. pylori infections. Here, we have used a Cag type IV secretion reporter assay for screening a repurposing compound library for inhibitors targeting this system. We found that the antitumor agent cisplatin, a platinum coordination complex that kills target cells by formation of DNA crosslinks, is a potent inhibitor of the Cag type IV secretion system. Strikingly, we found that this inhibitory activity of cisplatin depends on a ligand exchange reaction which incorporates a solvent molecule (dimethylsulfoxide) into the complex, a modification which is known to be deleterious for DNA crosslinking, and for its anticancer activity. We extended our analysis to several analogous platinum complexes containing N-heterocyclic carbene, as well as DMSO or other ligands, and found varying inhibitory activities toward the Cag system which were not congruent with their DNA-binding properties, suggesting that protein interactions may cause the inhibitory effect. Inhibition experiments under varying conditions revealed effects on adherence and bacterial viability as well, and showed that the type IV secretion-inhibitory capacity of platinum complexes can be inactivated by sulfur-containing reagents and in complex bacterial growth media. Taken together, our results demonstrate DNA binding-independent inhibitory effects of cisplatin and other platinum complexes against different H. pylori processes including type IV secretion.
2020-12-18T00:00:00ZA role for PchHI as the ABC transporter in iron acquisition by the siderophore pyochelin in Pseudomonas aeruginosa.Roche, BéatriceGarcia-Rivera, Mariel ANormant, VincentKuhn, LaurianeHammann, PhilippeBrönstrup, MarkMislin, Gaëtan L ASchalk, Isabelle Jhttp://hdl.handle.net/10033/6231152021-12-08T01:52:27Z2021-10-18T00:00:00ZA role for PchHI as the ABC transporter in iron acquisition by the siderophore pyochelin in Pseudomonas aeruginosa.
Roche, Béatrice; Garcia-Rivera, Mariel A; Normant, Vincent; Kuhn, Lauriane; Hammann, Philippe; Brönstrup, Mark; Mislin, Gaëtan L A; Schalk, Isabelle J
Iron is an essential nutrient for bacterial growth but poorly bioavailable. Bacteria scavenge ferric iron by synthesizing and secreting siderophores, small compounds with a high affinity for iron. Pyochelin (PCH) is one of the two siderophores produced by the opportunistic pathogen Pseudomonas aeruginosa. After capturing a ferric iron molecule, PCH-Fe is imported back into bacteria first by the outer membrane transporter FptA and then by the inner membrane permease FptX. Here, using molecular biology, 55 Fe uptake assays, and LC-MS/MS quantification, we first find a role for PchHI as the heterodimeric ABC transporter involved in the siderophore-free iron uptake into the bacterial cytoplasm. We also provide the first evidence that PCH is able to reach the bacterial periplasm and cytoplasm when both FptA and FptX are expressed. Finally, we detected an interaction between PchH and FptX, linking the ABC transporter PchHI with the inner permease FptX in the PCH-Fe uptake pathway. These results pave the way for a better understanding of the PCH siderophore pathway, giving future directions to tackle P. aeruginosa infections.
2021-10-18T00:00:00ZSelective Bacterial Targeting and Infection-Triggered Release of Antibiotic Colistin Conjugates.Tegge, WernerGuerra, GiuliaHöltke, AlexanderSchiller, LauritzBeutling, UlrikeHarmrolfs, KirstenGröbe, LotharWullenkord, HannahXu, ChunfaWeich, HerbertBrönstrup, Markhttp://hdl.handle.net/10033/6231052021-12-01T02:09:01Z2021-07-05T00:00:00ZSelective Bacterial Targeting and Infection-Triggered Release of Antibiotic Colistin Conjugates.
Tegge, Werner; Guerra, Giulia; Höltke, Alexander; Schiller, Lauritz; Beutling, Ulrike; Harmrolfs, Kirsten; Gröbe, Lothar; Wullenkord, Hannah; Xu, Chunfa; Weich, Herbert; Brönstrup, Mark
In order to render potent, but toxic antibiotics more selective, we have explored a novel conjugation strategy that includes drug accumulation followed by infection-triggered release of the drug. Bacterial targeting was achieved using a modified fragment of the human antimicrobial peptide ubiquicidin, as demonstrated by fluorophore-tagged variants. To limit the release of the effector colistin only to infection-related situations, we introduced a linker that was cleaved by neutrophil elastase (NE), an enzyme secreted by neutrophil granulocytes at infection sites. The linker carried an optimized sequence of amino acids that was required to assure sufficient cleavage efficiency. The antibacterial activity of five regioisomeric conjugates prepared by total synthesis was masked, but was released upon exposure to recombinant NE when the linker was attached to amino acids at the 1- or the 3-position of colistin. A proof-of-concept was achieved in co-cultures of primary human neutrophils and Escherichia coli that induced the secretion of NE, the release of free colistin, and an antibacterial efficacy that was equal to that of free colistin.
2021-07-05T00:00:00Z