Identification of an anti-Gram-negative bacteria agent disrupting the interaction between lipopolysaccharide transporters LptA and LptC
- Int J Antimicrob Agents. 2019 Apr;53(4):442-448. doi: 10.1016/j.ijantimicag.2018.11.016.
- 1. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 2. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 3. Department of Biomedical Sciences, College of Medicine, Florida State University, Tallahassee, FL, USA. Electronic address: [email protected].
- 4. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
- 5. Beijing Key Laboratory of Antimicrobial Agents, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: [email protected].
Introduction: 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.
Methods: 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.
Results: 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.
Conclusion: This study successfully identified, by using a yeast two-hybrid system, an Antibacterial agent that likely blocks LPS transport in Gram-negative bacteria.