title: Sensor histidine kinase is a β-lactam receptor and induces resistance to β-lactam antibiotics.
abstract: β-Lactams disrupt bacterial cell wall synthesis, and these agents are the most widely used antibiotics. One of the principle mechanisms by which bacteria resist the action of β-lactams is by producing β-lactamases, enzymes that degrade β-lactams. In Gram-negative bacteria, production of β-lactamases is often induced in response to the antibiotic-associated damage to the cell wall. Here, we have identified a previously unidentified mechanism that governs β-lactamase production. In the Gram-negative enteric pathogen Vibrio parahaemolyticus, we found a histidine kinase/response regulator pair (VbrK/VbrR) that controls expression of a β-lactamase. Mutants lacking either VbrK or VbrR do not produce the β-lactamase and are no longer resistant to β-lactam antibiotics. Notably, VbrK autophosphorylation is activated by β-lactam antibiotics, but not by other lactams. However, single amino acid substitutions in the putative periplasmic binding pocket of VbrK leads its phosphorylation in response to both β-lactam and other lactams, suggesting that this kinase is a β-lactam receptor that can directly detect β-lactam antibiotics instead of detecting the damage to cell wall resulting from β-lactams. In strong support of this idea, we found that purified periplasmic sensor domain of VbrK binds penicillin, and that such binding is critical for VbrK autophosphorylation and β-lactamase production. Direct recognition of β-lactam antibiotics by a histidine kinase receptor may represent an evolutionarily favorable mechanism to defend against β-lactam antibiotics.
authors.affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269-3089;
authors.forename: Lu
authors.initials: L
authors.lastname: Li
authors.affiliation: State Key Laboratory of Bioreactor Engineering, School of Biotechnology, East China University of Science and Technology, Shanghai 200237, China;
authors.forename: Qiyao
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269-3089; Jiangsu Academy of Agricultural Sciences, Nanjing 210014, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Shanghai-Ministry of Science and Technology (MOST) Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai 201203, China.
authors.forename: Minjun
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269-3089;
authors.forename: Mazhar I
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Pathobiology and Veterinary Science, University of Connecticut, Storrs, CT 06269-3089; xiaohui.zhou@uconn.edu.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D002228:Carbenicillin / Q000494:pharmacology; D017124:Conserved Sequence; D004352:Drug Resistance, Microbial / Q000187:drug effects*; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D000071677:Histidine Kinase; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D017423:Sequence Analysis, RNA; D013379:Substrate Specificity / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014736:Vibrio parahaemolyticus / Q000187:drug effects / Q000235:genetics; D001618:beta-Lactamases / Q000378:metabolism; D047090:beta-Lactams / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008565:Membrane Proteins; D047090:beta-Lactams; D011494:Protein Kinases; D000071677:Histidine Kinase; D001618:beta-Lactamases; D002228:Carbenicillin
keywords: Vibrio; histidine kinase; β-lactam receptor; β-lactamase
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