文献类型：期刊文献

英文题名：Role of Berberine as a Potential Efflux Pump Inhibitor against MdfA from Escherichia coli: In Vitro and In Silico Studies

作者：Li, Ying[1];Ge, Xizhen[1]

第一作者：李映

通讯作者：Ge, XZ[1]

机构：[1]Beijing Union Univ, Coll Biochem Engn, Beijing, Peoples R China

第一机构：北京联合大学生物化学工程学院

通讯机构：[1]corresponding author), Beijing Union Univ, Coll Biochem Engn, Beijing, Peoples R China.|[1141726]北京联合大学生物化学工程学院;[11417]北京联合大学;

年份：2023

卷号：11

期号：2

外文期刊名：MICROBIOLOGY SPECTRUM

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000984528600139)】；

基金：This work was financially supported by a project of Beijing Municipal Commission of Education (KZ201911417049).

语种：英文

外文关键词：berberine; efflux pump; inhibitor; salt bridge; conformational transition

摘要：In this work, we evaluated the role of berberine (BBR) as an inhibitor of the MFS efflux pump MdfA from E. coli. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. Infections by Gram-negative pathogens are usually difficult to manage due to the drug export by efflux pumps. With the evolution and horizontal transfer of efflux pumps, there is an urgent need to discover safe and effective efflux pump inhibitors. Here, we found that the natural compound berberine (BBR), a traditional medicine for intestinal infection, is an inhibitor against the major facilitator superfamily (MFS) efflux pump MdfA in Escherichia coli. The impact of BBR on MdfA was evaluated in a recombinant E. coli reporter strain. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. At the same time, we conducted molecular dynamics simulations to investigate the mechanisms of BBR's effect on MdfA. Our data indicated that BBR can aggregate to the periplasmic and cytoplasmic sides of MdfA in both of its inward and outward conformations. Protein rigidities were affected to different degrees. More importantly, two major driving forces for the conformational transition, salt bridges and hydrophilic interactions with water, were changed by BBR's aggregation to MdfA, which affected its conformational transition. In summary, our data provide evidence for the extended application of BBR as an efflux pump inhibitor at a clinically meaningful level. We also reveal the mechanisms and provide insights into BBR's effect on the reciprocal motion of MdfA. IMPORTANCE In this work, we evaluated the role of berberine (BBR) as an inhibitor of the MFS efflux pump MdfA from E. coli. We demonstrated that low levels of BBR significantly increased intracellular ciprofloxacin concentrations and restored antibiotic susceptibility of the reporter strain. Molecular dynamics simulations revealed the effect of BBR on the conformational transition of MdfA. Our data suggested that driving forces for MdfA's conformational transition were affected by BBR and provided evidence for BBR's extended application as an effective inhibitor of MdfA.