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Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC
The need for novel antibiotics has become imperative with the increasing prevalence of antibiotic resistance in Gram-negative bacteria in clinics. Acting as a permeability barrier, lipopolysaccharide (LPS) protects Gram-negative bacteria against drugs. LPS is synthesized in cells and transported to...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598311/ https://www.ncbi.nlm.nih.gov/pubmed/36290043 http://dx.doi.org/10.3390/antibiotics11101385 |
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author | Dai, Xiaowei Yuan, Min Lu, Yu Zhu, Xiaohong Liu, Chao Zheng, Yifan Si, Shuyi Yuan, Lijie Zhang, Jing Li, Yan |
author_facet | Dai, Xiaowei Yuan, Min Lu, Yu Zhu, Xiaohong Liu, Chao Zheng, Yifan Si, Shuyi Yuan, Lijie Zhang, Jing Li, Yan |
author_sort | Dai, Xiaowei |
collection | PubMed |
description | The need for novel antibiotics has become imperative with the increasing prevalence of antibiotic resistance in Gram-negative bacteria in clinics. Acting as a permeability barrier, lipopolysaccharide (LPS) protects Gram-negative bacteria against drugs. LPS is synthesized in cells and transported to the outer membrane (OM) via seven lipopolysaccharide transport (Lpt) proteins (LptA–LptG). Of these seven Lpt proteins, LptC interacts with LptA to transfer LPS from the inner membrane (IM) to the OM, and assembly is aided by LptD/LptE. This interaction among the Lpt proteins is important for the biosynthesis of LPS; therefore, the Lpt proteins, which are significant in the assembly process of LPS, can be a potential target for new antibiotics. In this study, a yeast two-hybrid (Y2H) system was used to screen compounds that could block LPS transport by inhibiting LptA/LptC interaction, which finally disrupts the biosynthesis of the OM. We selected the compound IMB-0042 for this study. Our results suggest that IMB-0042 disrupts LptA/LptC interaction by binding to both LptA and LptC. Escherichia coli cells, when treated with IMB-0042, showed filament morphology, impaired OM integrity, and an accumulation of LPS in the periplasm. IMB-0042 inhibited the growth of Gram-negative bacteria and showed synergistic sensitization to other antibiotics, with low cytotoxicity. Thus, we successfully identified a potential antibacterial agent by using a Y2H system, which blocks the transport of LPS by targeting LptA/LptC interaction in Escherichia coli. |
format | Online Article Text |
id | pubmed-9598311 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-95983112022-10-27 Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC Dai, Xiaowei Yuan, Min Lu, Yu Zhu, Xiaohong Liu, Chao Zheng, Yifan Si, Shuyi Yuan, Lijie Zhang, Jing Li, Yan Antibiotics (Basel) Article The need for novel antibiotics has become imperative with the increasing prevalence of antibiotic resistance in Gram-negative bacteria in clinics. Acting as a permeability barrier, lipopolysaccharide (LPS) protects Gram-negative bacteria against drugs. LPS is synthesized in cells and transported to the outer membrane (OM) via seven lipopolysaccharide transport (Lpt) proteins (LptA–LptG). Of these seven Lpt proteins, LptC interacts with LptA to transfer LPS from the inner membrane (IM) to the OM, and assembly is aided by LptD/LptE. This interaction among the Lpt proteins is important for the biosynthesis of LPS; therefore, the Lpt proteins, which are significant in the assembly process of LPS, can be a potential target for new antibiotics. In this study, a yeast two-hybrid (Y2H) system was used to screen compounds that could block LPS transport by inhibiting LptA/LptC interaction, which finally disrupts the biosynthesis of the OM. We selected the compound IMB-0042 for this study. Our results suggest that IMB-0042 disrupts LptA/LptC interaction by binding to both LptA and LptC. Escherichia coli cells, when treated with IMB-0042, showed filament morphology, impaired OM integrity, and an accumulation of LPS in the periplasm. IMB-0042 inhibited the growth of Gram-negative bacteria and showed synergistic sensitization to other antibiotics, with low cytotoxicity. Thus, we successfully identified a potential antibacterial agent by using a Y2H system, which blocks the transport of LPS by targeting LptA/LptC interaction in Escherichia coli. MDPI 2022-10-10 /pmc/articles/PMC9598311/ /pubmed/36290043 http://dx.doi.org/10.3390/antibiotics11101385 Text en © 2022 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 Dai, Xiaowei Yuan, Min Lu, Yu Zhu, Xiaohong Liu, Chao Zheng, Yifan Si, Shuyi Yuan, Lijie Zhang, Jing Li, Yan Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title | Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title_full | Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title_fullStr | Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title_full_unstemmed | Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title_short | Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC |
title_sort | identification of a small molecule that inhibits the interaction of lps transporters lpta and lptc |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598311/ https://www.ncbi.nlm.nih.gov/pubmed/36290043 http://dx.doi.org/10.3390/antibiotics11101385 |
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