title: Novobiocin binding to NalD induces the expression of the MexAB-OprM pump in Pseudomonas aeruginosa.
abstract: NalD was reported to be the secondary repressor of the MexAB-OprM multidrug efflux pump, the major system contributing to intrinsic multidrug resistance in Pseudomonas aeruginosa. Here, we show that novobiocin binds directly to NalD, which leads NalD to dissociate from the DNA promoter, and thus de-represses the expression of the MexAB-OprM pump. In addition, we have solved the crystal structure of NalD at a resolution of 2.90 Å. The structural alignment of NalD to its homologue TtgR reveals that the residues N129 and H167 in NalD are involved in its novobiocin-binding ability. We have confirmed the function of these two amino acids by EMSA and plate assay. The results presented here highlight the importance and diversity of regulatory mechanism in bacterial antibiotic resistance, and provide further insight for novel antimicrobial development.
authors: Department of Chemical Physics, University of Science and Technology of China, Hefei, 230026, China.|State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Weizhong
authors: W
authors: Chen
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Dan
authors: D
authors: Wang
authors: Department of Urology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210093, China.
authors: Wenquan
authors: W
authors: Zhou
authors: Department of Dermatology, Jinling Hospital, School of Medicine, Nanjing University, Nanjing, 210093, China.
authors: Hong
authors: H
authors: Sang
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Xichun
authors: X
authors: Liu
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Zhiyun
authors: Z
authors: Ge
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Jin
authors: J
authors: Zhang
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Lefu
authors: L
authors: Lan
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
authors: Cai-Guang
authors: CG
authors: Yang
authors: State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Chemistry for Life Sciences, Nanjing University, Nanjing, 210093, China.
authors: Hao
authors: H
authors: Chen
mesh_terms: D001426:Bacterial Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D003460:Crystallization; D018360:Crystallography, X-Ray; D024901:Drug Resistance, Multiple, Bacterial; D015964:Gene Expression Regulation, Bacterial; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009675:Novobiocin / Q000737:chemistry / Q000378:metabolism*; D009876:Operon; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D011550:Pseudomonas aeruginosa / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D026901:Membrane Transport Proteins; D012097:Repressor Proteins; D009675:Novobiocin