Prof. Jiang Xukai’s team from the National Glycoengineering Research Center at Shandong University has recently made a significant discovery in understanding the mechanisms of bacterial resistance. Their study, titled "Membrane lipid homeostasis dually regulates the conformational transition of phosphoethanolamine transferase EptA," was published in the renowned journalNature Communications.

The emergence of multidrug-resistant Gram-negative bacteria has become a major global health concern. The outer membrane of these bacteria, which contains lipopolysaccharides (LPS), plays a crucial role in protecting them and conferring antibiotic resistance. EptA, an important LPS-modifying enzyme, uses phosphatidylethanolamine (PE) in the cell membrane to modify LPS, thereby enhancing bacterial resistance. However, the regulatory mechanism of EptA has remained elusive.

The research team employed microsecond-scale all-atom molecular dynamics simulations to investigate the conformational changes of EptA during catalysis. They found that the conformation of EptA oscillates between closed and open states, allowing for the precise binding of substrates. The binding of PE to EptA promotes its conformational transition by altering the interactions between its domains. Interestingly, the surrounding lipid microenvironment, especially the PE proportion in the membrane, significantly affects the conformation of EptA. PE-rich conditions stabilize the open conformation of EptA through both orthosteric and allosteric effects.

As EptA catalyzes, it depletes membrane PE, hindering its activity. This led to a "self-promoted model" where membrane lipid homeostasis, particularly PE content, regulates EptA. This ensures EptA activation only with enough PE, preventing excessive depletion. The research offers insights into bacterial outer membrane remodeling and a potential target for new antibiotics.

The research was supported by the National Key Research and Development Program of China and the National Natural Science Foundation of China.