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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MDPI AG
2022-10-01
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| Series: | Antibiotics |
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| Online Access: | https://www.mdpi.com/2079-6382/11/10/1385 |
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| author | Xiaowei Dai Min Yuan Yu Lu Xiaohong Zhu Chao Liu Yifan Zheng Shuyi Si Lijie Yuan Jing Zhang Yan Li |
| author_facet | Xiaowei Dai Min Yuan Yu Lu Xiaohong Zhu Chao Liu Yifan Zheng Shuyi Si Lijie Yuan Jing Zhang Yan Li |
| author_sort | Xiaowei Dai |
| collection | DOAJ |
| 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. <i>Escherichia coli</i> 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 <i>Escherichia coli</i>. |
| first_indexed | 2024-03-09T20:50:42Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 2079-6382 |
| language | English |
| last_indexed | 2024-03-09T20:50:42Z |
| publishDate | 2022-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antibiotics |
| spelling | doaj.art-7ea6d04e1035475c851cce4148952cf42023-11-23T22:35:34ZengMDPI AGAntibiotics2079-63822022-10-011110138510.3390/antibiotics11101385Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptCXiaowei Dai0Min Yuan1Yu Lu2Xiaohong Zhu3Chao Liu4Yifan Zheng5Shuyi Si6Lijie Yuan7Jing Zhang8Yan Li9Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaState Key Laboratory for Infectious Diseases Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Disease, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing 102206, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaHebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan 063210, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaKey Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, ChinaThe 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. <i>Escherichia coli</i> 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 <i>Escherichia coli</i>.https://www.mdpi.com/2079-6382/11/10/1385lipopolysaccharidelipopolysaccharide transport (Lpt) protein<i>Escherichia coli</i>LptA/LptC interactionyeast two-hybridantibacterial agent |
| spellingShingle | Xiaowei Dai Min Yuan Yu Lu Xiaohong Zhu Chao Liu Yifan Zheng Shuyi Si Lijie Yuan Jing Zhang Yan Li Identification of a Small Molecule That Inhibits the Interaction of LPS Transporters LptA and LptC Antibiotics lipopolysaccharide lipopolysaccharide transport (Lpt) protein <i>Escherichia coli</i> LptA/LptC interaction yeast two-hybrid antibacterial agent |
| 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 | lipopolysaccharide lipopolysaccharide transport (Lpt) protein <i>Escherichia coli</i> LptA/LptC interaction yeast two-hybrid antibacterial agent |
| url | https://www.mdpi.com/2079-6382/11/10/1385 |
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