title: Stenotrophomonas maltophilia PhoP, a Two-Component Response Regulator, Involved in Antimicrobial Susceptibilities.
abstract: Stenotrophomonas maltophilia, a gram-negative bacterium, has increasingly emerged as an important nosocomial pathogen. It is well-known for resistance to a variety of antimicrobial agents including cationic antimicrobial polypeptides (CAPs). Resistance to polymyxin B, a kind of CAPs, is known to be controlled by the two-component system PhoPQ. To unravel the role of PhoPQ in polymyxin B resistance of S. maltophilia, a phoP mutant was constructed. We found MICs of polymyxin B, chloramphenicol, ampicillin, gentamicin, kanamycin, streptomycin and spectinomycin decreased 2-64 fold in the phoP mutant. Complementation of the phoP mutant by the wild-type phoP gene restored all of the MICs to the wild type levels. Expression of PhoP was shown to be autoregulated and responsive to Mg2+ levels. The polymyxin B and gentamicin killing tests indicated that pretreatment of low Mg2+ can protect the wild-type S. maltophilia from killing but not phoP mutant. Interestingly, we found phoP mutant had a decrease in expression of SmeZ, an efflux transporter protein for aminoglycosides in S. maltophilia. Moreover, phoP mutant showed increased permeability in the cell membrane relative to the wild-type. In summary, we demonstrated the two-component regulator PhoP of S. maltophilia is involved in antimicrobial susceptibilities and low Mg2+ serves as a signal for triggering the pathway. Both the alteration in membrane permeability and downregulation of SmeZ efflux transporter in the phoP mutant contributed to the increased drug susceptibilities of S. maltophilia, in particular for aminoglycosides. This is the first report to describe the role of the Mg2+-sensing PhoP signaling pathway of S. maltophilia in regulation of the SmeZ efflux transporter and in antimicrobial susceptibilities. This study suggests PhoPQ TCS may serve as a target for development of antimicrobial agents against multidrug-resistant S. maltophilia.
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Ming-Che
authors.initials: MC
authors.lastname: Liu
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Lin
authors.initials: YL
authors.lastname: Tsai
authors.affiliation: Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Wei
authors.initials: YW
authors.lastname: Huang
authors.affiliation: Department of Clinical Pathology, Taipei City Hospital Renai Branch, Taipei, Taiwan, Republic of China.
authors.forename: Hsing-Yu
authors.initials: HY
authors.lastname: Chen
authors.affiliation: Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Po-Ren
authors.initials: PR
authors.lastname: Hsueh
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Szu-Yu
authors.initials: SY
authors.lastname: Lai
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Li-Chia
authors.initials: LC
authors.lastname: Chen
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Yi-Hwa
authors.initials: YH
authors.lastname: Chou
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.
authors.forename: Wen-Yuan
authors.initials: WY
authors.lastname: Lin
authors.affiliation: Department and Graduate Institute of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan, Republic of China.|Department of Laboratory Medicine, National Taiwan University Hospital, Taipei, Taiwan, Republic of China.
authors.forename: Shwu-Jen
authors.initials: SJ
authors.lastname: Liaw
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001426:Bacterial Proteins / Q000502:physiology*; D002463:Cell Membrane Permeability / Q000187:drug effects; D008274:Magnesium / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D020615:Stenotrophomonas maltophilia / Q000502:physiology*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008274:Magnesium