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Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology

Over the course of the last decades, the continuous exposure of bacteria to antibiotics—at least in parts due to misprescription, misuse, and misdosing—has led to the widespread development of antimicrobial resistances. This development poses a threat to the available medication in losing their effe...

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Autores principales: Revilla-Guarinos, Ainhoa, Popp, Philipp F., Dürr, Franziska, Lozano-Cruz, Tania, Hartig, Johanna, de la Mata, Francisco Javier, Gómez, Rafael, Mascher, Thorsten
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9459136/
https://www.ncbi.nlm.nih.gov/pubmed/36090105
http://dx.doi.org/10.3389/fmicb.2022.912536
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author Revilla-Guarinos, Ainhoa
Popp, Philipp F.
Dürr, Franziska
Lozano-Cruz, Tania
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
author_facet Revilla-Guarinos, Ainhoa
Popp, Philipp F.
Dürr, Franziska
Lozano-Cruz, Tania
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
author_sort Revilla-Guarinos, Ainhoa
collection PubMed
description Over the course of the last decades, the continuous exposure of bacteria to antibiotics—at least in parts due to misprescription, misuse, and misdosing—has led to the widespread development of antimicrobial resistances. This development poses a threat to the available medication in losing their effectiveness in treating bacterial infections. On the drug development side, only minor advances have been made to bring forward novel therapeutics. In addition to increasing the efforts and approaches of tapping the natural sources of new antibiotics, synthetic approaches to developing novel antimicrobials are being pursued. In this study, BDTL049 was rationally designed using knowledge based on the properties of natural antibiotics. BDTL049 is a carbosilane dendritic system with bow-tie type topology, which has antimicrobial activity at concentrations comparable to clinically established natural antibiotics. In this report, we describe its mechanism of action on the Gram-positive model organism Bacillus subtilis. Exposure to BDTL049 resulted in a complex transcriptional response, which pointed toward disturbance of the cell envelope homeostasis accompanied by disruption of other central cellular processes of bacterial metabolism as the primary targets of BDTL049 treatment. By applying a combination of whole-cell biosensors, molecular staining, and voltage sensitive dyes, we demonstrate that the mode of action of BDTL049 comprises membrane depolarization concomitant with pore formation. As a result, this new molecule kills Gram-positive bacteria within minutes. Since BDTL049 attacks bacterial cells at different targets simultaneously, this might decrease the chances for the development of bacterial resistances, thereby making it a promising candidate for a future antimicrobial agent.
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spelling pubmed-94591362022-09-10 Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology Revilla-Guarinos, Ainhoa Popp, Philipp F. Dürr, Franziska Lozano-Cruz, Tania Hartig, Johanna de la Mata, Francisco Javier Gómez, Rafael Mascher, Thorsten Front Microbiol Microbiology Over the course of the last decades, the continuous exposure of bacteria to antibiotics—at least in parts due to misprescription, misuse, and misdosing—has led to the widespread development of antimicrobial resistances. This development poses a threat to the available medication in losing their effectiveness in treating bacterial infections. On the drug development side, only minor advances have been made to bring forward novel therapeutics. In addition to increasing the efforts and approaches of tapping the natural sources of new antibiotics, synthetic approaches to developing novel antimicrobials are being pursued. In this study, BDTL049 was rationally designed using knowledge based on the properties of natural antibiotics. BDTL049 is a carbosilane dendritic system with bow-tie type topology, which has antimicrobial activity at concentrations comparable to clinically established natural antibiotics. In this report, we describe its mechanism of action on the Gram-positive model organism Bacillus subtilis. Exposure to BDTL049 resulted in a complex transcriptional response, which pointed toward disturbance of the cell envelope homeostasis accompanied by disruption of other central cellular processes of bacterial metabolism as the primary targets of BDTL049 treatment. By applying a combination of whole-cell biosensors, molecular staining, and voltage sensitive dyes, we demonstrate that the mode of action of BDTL049 comprises membrane depolarization concomitant with pore formation. As a result, this new molecule kills Gram-positive bacteria within minutes. Since BDTL049 attacks bacterial cells at different targets simultaneously, this might decrease the chances for the development of bacterial resistances, thereby making it a promising candidate for a future antimicrobial agent. Frontiers Media S.A. 2022-08-26 /pmc/articles/PMC9459136/ /pubmed/36090105 http://dx.doi.org/10.3389/fmicb.2022.912536 Text en Copyright © 2022 Revilla-Guarinos, Popp, Dürr, Lozano-Cruz, Hartig, de la Mata, Gómez and Mascher. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Microbiology
Revilla-Guarinos, Ainhoa
Popp, Philipp F.
Dürr, Franziska
Lozano-Cruz, Tania
Hartig, Johanna
de la Mata, Francisco Javier
Gómez, Rafael
Mascher, Thorsten
Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title_full Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title_fullStr Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title_full_unstemmed Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title_short Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
title_sort synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
topic Microbiology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9459136/
https://www.ncbi.nlm.nih.gov/pubmed/36090105
http://dx.doi.org/10.3389/fmicb.2022.912536
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