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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...

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Autores principales: Dai, Xiaowei, Yuan, Min, Lu, Yu, Zhu, Xiaohong, Liu, Chao, Zheng, Yifan, Si, Shuyi, Yuan, Lijie, Zhang, Jing, Li, Yan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
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.
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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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