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The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants

The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antib...

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Autores principales: Popp, Philipp F., Lozano-Cruz, Tania, Dürr, Franziska, Londaitsbehere, Addis, Hartig, Johanna, de la Mata, Francisco Javier, Gómez, Rafael, Mascher, Thorsten, Revilla-Guarinos, Ainhoa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866484/
https://www.ncbi.nlm.nih.gov/pubmed/36678925
http://dx.doi.org/10.3390/pharmaceutics15010297
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author Popp, Philipp F.
Lozano-Cruz, Tania
Dürr, Franziska
Londaitsbehere, Addis
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
Revilla-Guarinos, Ainhoa
author_facet Popp, Philipp F.
Lozano-Cruz, Tania
Dürr, Franziska
Londaitsbehere, Addis
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
Revilla-Guarinos, Ainhoa
author_sort Popp, Philipp F.
collection PubMed
description The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antibacterial compounds. Hereby, carbosilane dendritic systems that exhibit antimicrobial properties have the potential to serve as synthetic and rationally designed molecules for therapeutic use. The bow-tie type topology of BDTL049 was recently investigated against the Gram-positive model organism Bacillus subtilis, revealing strong bactericidal properties. In this study, we follow up on open questions concerning the usability of BDTL049. For this, we synthesized a fluorescent-labeled version of BDTL049 that maintained all antimicrobial features to unravel the interaction of the compound and bacterial membrane. Subsequently, we highlight the bacterial sensitivity against BDTL049 by performing a mutational study of known resistance determinants. Finally, we address the cytotoxicity of the compound in human cells, unexpectedly revealing a high sensitivity of the eukaryotic cells upon BDTL049 exposure. The insights presented here further elaborate on the unique features of BDTL049 as a promising candidate as an antimicrobial agent while not precluding that further rounds of rational designing are needed to decrease cytotoxicity to ultimately pave the way for synthetic antibiotics toward clinical applicability.
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spelling pubmed-98664842023-01-22 The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants Popp, Philipp F. Lozano-Cruz, Tania Dürr, Franziska Londaitsbehere, Addis Hartig, Johanna de la Mata, Francisco Javier Gómez, Rafael Mascher, Thorsten Revilla-Guarinos, Ainhoa Pharmaceutics Article The threat of antimicrobial-resistant bacteria is ever increasing and over the past-decades development of novel therapeutic counter measurements have virtually come to a halt. This circumstance calls for interdisciplinary approaches to design, evaluate and validate the mode of action of novel antibacterial compounds. Hereby, carbosilane dendritic systems that exhibit antimicrobial properties have the potential to serve as synthetic and rationally designed molecules for therapeutic use. The bow-tie type topology of BDTL049 was recently investigated against the Gram-positive model organism Bacillus subtilis, revealing strong bactericidal properties. In this study, we follow up on open questions concerning the usability of BDTL049. For this, we synthesized a fluorescent-labeled version of BDTL049 that maintained all antimicrobial features to unravel the interaction of the compound and bacterial membrane. Subsequently, we highlight the bacterial sensitivity against BDTL049 by performing a mutational study of known resistance determinants. Finally, we address the cytotoxicity of the compound in human cells, unexpectedly revealing a high sensitivity of the eukaryotic cells upon BDTL049 exposure. The insights presented here further elaborate on the unique features of BDTL049 as a promising candidate as an antimicrobial agent while not precluding that further rounds of rational designing are needed to decrease cytotoxicity to ultimately pave the way for synthetic antibiotics toward clinical applicability. MDPI 2023-01-16 /pmc/articles/PMC9866484/ /pubmed/36678925 http://dx.doi.org/10.3390/pharmaceutics15010297 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Popp, Philipp F.
Lozano-Cruz, Tania
Dürr, Franziska
Londaitsbehere, Addis
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
Revilla-Guarinos, Ainhoa
The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title_full The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title_fullStr The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title_full_unstemmed The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title_short The Novel Synthetic Antibiotic BDTL049 Based on a Dendritic System Induces Lipid Domain Formation while Escaping the Cell Envelope Stress Resistance Determinants
title_sort novel synthetic antibiotic bdtl049 based on a dendritic system induces lipid domain formation while escaping the cell envelope stress resistance determinants
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9866484/
https://www.ncbi.nlm.nih.gov/pubmed/36678925
http://dx.doi.org/10.3390/pharmaceutics15010297
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