title: Identification and functional characterization of Penicillium marneffei pleiotropic drug resistance transporters ABC1 and ABC2.
abstract: Penicilliosis caused by the dimorphic fungus Penicillium marneffei is an endemic, AIDS-defining illness and, after tuberculosis and cryptococcosis, the third most common opportunistic infection of AIDS patients in tropical Southeast Asia. Untreated, patients have poor prognosis; however, primary amphotericin B treatment followed by prolonged itraconazole prophylaxis is effective. To identify ATP-binding cassette (ABC) transporters that may play a role in potential multidrug resistance of P. marneffei, we identified and classified all 46 P. marneffei ABC transporters from the genome sequence. PmABC1 and PmABC2 were most similar to the archetype Candida albicans multidrug efflux pump gene CDR1. P. marneffei Abc1p (PmAbc1p) was functionally expressed in Saccharomyces cerevisiae, although at rather low levels, and correctly localized to the plasma membrane, causing cells to be fourfold to eightfold more resistant to azoles and many other xenobiotics than untransformed cells. P. marneffei Abc2p (PmAbc2p) was expressed at similarly low levels, but it had no efflux activity and did not properly localize to the plasma membrane. Interestingly, PmAbc1p mislocalized and lost its transport activity when cells were shifted to 37 °C. We conclude that expression of PmAbc1p in S. cerevisiae confers resistance to several xenobiotics indicating that PmAbc1p may be a multidrug efflux pump.
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Japan.
authors.forename: Siribun
authors.initials: S
authors.lastname: Panapruksachat
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Japan.
authors.forename: Shun
authors.initials: S
authors.lastname: Iwatani
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Oura
authors.affiliation: Faculty of Medicine, Chiang Mai University, Thailand.
authors.forename: Nongnuch
authors.initials: N
authors.lastname: Vanittanakom
authors.affiliation: Faculty of Medicine, Chulalongkorn University, Thailand.
authors.forename: Ariya
authors.initials: A
authors.lastname: Chindamporn
authors.affiliation: Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, New Zealand.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Niimi
authors.affiliation: Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, New Zealand.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Niimi
authors.affiliation: Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, New Zealand.
authors.forename: Erwin
authors.initials: E
authors.lastname: Lamping
authors.affiliation: Sir John Walsh Research Institute, Faculty of Dentistry, University of Otago, New Zealand.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Cannon
authors.affiliation: Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Japan skajiwar@bio.titech.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Kajiwara
mesh_terms: D000935:Antifungal Agents / Q000378:metabolism* / Q000494:pharmacology*; D001210:Asia, Southeastern; D003001:Cloning, Molecular; D025141:Drug Resistance, Fungal; D015870:Gene Expression; D016681:Genome, Fungal; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D010407:Penicillium / Q000235:genetics* / Q000302:isolation & purification / Q000378:metabolism*; D021381:Protein Transport; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics
chemical_list: D000935:Antifungal Agents; D026901:Membrane Transport Proteins
keywords: ABC transporters; PDR transporters; multidrug efflux pumps; multidrug resistance; pathogenic fungus