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

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung

Beitragende

  • Ainhoa Revilla-Guarinos - , Professur für Physikalische Chemie, Technische Universität Dresden, Oral Microbiome Group, FISABIO Foundation (Autor:in)
  • Philipp F. Popp - , Professur für Allgemeine Mikrobiologie, Technische Universität Dresden, Oral Microbiome Group, FISABIO Foundation (Autor:in)
  • Franziska Dürr - , Professur für Allgemeine Mikrobiologie, Technische Universität Dresden (Autor:in)
  • Tania Lozano-Cruz - , University of Alcalá, Ramón y Cajal Health Research Institute, CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Johanna Hartig - , Technische Universität Dresden (Autor:in)
  • Francisco Javier de la Mata - , University of Alcalá, Ramón y Cajal Health Research Institute, CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Rafael Gómez - , University of Alcalá, Ramón y Cajal Health Research Institute, CIBER - Centro de Investigación Biomédica en Red (Autor:in)
  • Thorsten Mascher - , Professur für Allgemeine Mikrobiologie, Technische Universität Dresden (Autor:in)

Abstract

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.

Details

OriginalspracheEnglisch
Aufsatznummer912536
FachzeitschriftFrontiers in microbiology
Jahrgang13
Ausgabenummer13
PublikationsstatusVeröffentlicht - 26 Aug. 2022
Peer-Review-StatusJa

Externe IDs

PubMed 36090105
Mendeley 44c4358d-201c-3fed-a78e-e8ccc7403ead

Schlagworte

Schlagwörter

  • antimicrobial resistance, Bacillus subtilis, carbosilane dendritic system, cell envelope stress response, drug design, mode of action, whole-cell biosensors

Bibliotheksschlagworte