Identification of an anti-Gram-negative bacteria agent disrupting the interaction between lipopolysaccharide transporters LptA and LptC

• Published in: International journal of antimicrobial agents 2019-04, Vol.53 (4), p.442-448
• Main Authors: Zhang, Xuelian, Li, Yan, Wang, Weiwei, Zhang, Jing, Lin, Yuan, Hong, Bin, You, Xuefu, Song, Danqing, Wang, Yanchang, Jiang, Jiandong, Si, Shuyi
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacology; Antibacterial agent; Biological Transport - drug effects; Carrier Proteins - metabolism; Drug Resistance, Multiple, Bacterial - genetics; Escherichia coli; Escherichia coli - drug effects; Escherichia coli - genetics; Escherichia coli Infections - drug therapy; Escherichia coli Proteins - metabolism; Lipopolysaccharide; Lipopolysaccharides - metabolism; LptA-LptC interaction; Membrane Proteins - metabolism; Surface Plasmon Resonance; Yeast two-hybrid
• ISSN: 0924-8579; 1872-7913
• DOI: 10.1016/j.ijantimicag.2018.11.016

•Gram-negative bacteria lipopolysaccharide transport and assembly are attractive targets for novel antibiotics.•A yeast two-hybrid system was established to detect LptA-LptC interaction and to screen compounds that interfere with such interaction.•Compound IMB-881 was found to block this interaction of LptA-LptC and showed potent antibacterial activity against Gram-negative bacteria.•This compound disrupts LptA-LptC by specifically binding to LptA. Escherichia coli cells treated with this compound exhibited pronounced filament morphology. The emergence of drug-resistant Gram-negative bacteria is a serious clinical problem that causes increased morbidity and mortality. However, the slow discovery of new antibiotics is unable to meet the need for treating bacterial infections caused by drug-resistant strains. Lipopolysaccharide (LPS) is synthesized in the cytoplasm and transported to the cell envelope by the LPS transport (Lpt) system. LptA and LptC form a complex that transports LPS from the inner membrane to the outer membrane. This study performed a screen for agents that disrupt the transport of LPS in Gram-negative bacteria Escherichia coli. It established a yeast two-hybrid system to detect LptA-LptC interaction and used this system to identify a compound, IMB-881, that blocks this interaction and shows antibacterial activity. This study demonstrated that the IMB-881 compound specifically binds to LptA to disrupt LptA-LptC interaction using surface plasmon resonance assay. Overproduction of LptA protein but not that of LptC lowered the antibacterial activity of IMB-881. Strikingly, Escherichia coli cells accumulated ‘extra’ membrane material in the periplasm and exhibited filament morphology after treatment with IMB-881. This study successfully identified, by using a yeast two-hybrid system, an antibacterial agent that likely blocks LPS transport in Gram-negative bacteria.