Synthesis and mechanism-of-action of a novel synthetic antibiotic based on a dendritic system with bow-tie topology
Por:
Revilla-Guarinos, A, Popp, P, Durr, F, Lozano-Cruz, T, Hartig, J, de la Mata, F, Gomez, R and Mascher, T
Publicada:
26 ago 2022
Resumen:
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.
Filiaciones:
:
Tech Univ Dresden, Inst Mikrobiol, Dept Gen Microbiol, Dresden, Germany
FISABIO Fdn, Oral Microbiome Grp, Genom & Hlth Dept, Valencia, Spain
Popp, P:
Tech Univ Dresden, Inst Mikrobiol, Dept Gen Microbiol, Dresden, Germany
Humboldt Univ, Inst Biol Bacterial Physiol, Berlin, Germany
Durr, F:
Tech Univ Dresden, Inst Mikrobiol, Dept Gen Microbiol, Dresden, Germany
Lozano-Cruz, T:
Univ Alcala, Res Inst Chem Andres M Del Rio IQAR, Dept Organ & Inorgan Chem, Madrid, Spain
Ramon Y Cajal Hlth Res Inst IRYCIS, Madrid, Spain
Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Madrid, Spain
Hartig, J:
Tech Univ Dresden, Inst Mikrobiol, Dept Gen Microbiol, Dresden, Germany
de la Mata, F:
Univ Alcala, Res Inst Chem Andres M Del Rio IQAR, Dept Organ & Inorgan Chem, Madrid, Spain
Ramon Y Cajal Hlth Res Inst IRYCIS, Madrid, Spain
Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Madrid, Spain
Gomez, R:
Univ Alcala, Res Inst Chem Andres M Del Rio IQAR, Dept Organ & Inorgan Chem, Madrid, Spain
Ramon Y Cajal Hlth Res Inst IRYCIS, Madrid, Spain
Networking Res Ctr Bioengn Biomat & Nanomed CIBER, Madrid, Spain
Mascher, T:
Tech Univ Dresden, Inst Mikrobiol, Dept Gen Microbiol, Dresden, Germany
Green Published, gold
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