title: RfiA, a novel PAP2 domain-containing polytopic membrane protein that confers resistance to the FtsZ inhibitor PC190723.
abstract: BACKGROUND
  As an essential protein for bacterial cell division, the tubulin-like FtsZ protein has been selected as a target for development of next generation antimicrobials. PC190723 is a fluoride-containing benzamide compound developed as a FtsZ inhibitor that selectively inhibits growth of multidrug resistant Gram-positive bacteria.
  
  
  OBJECTIVE
  Our aim was to investigate the mechanism of resistance to PC109723 conferred by over-expression of a gene, rfiA, in an environmental bacterium Arthrobacter A3.
  
  
  METHODS
  The investigations included analysis of the effect of PC109723 on wild-type Arthrobacter A3 and a recombinant strain over-expressing rfiA, in vivo localization of RfiA, in vitro measurements of fluorine release from PC109723 by membrane extracts from the over-expression strain combined with mass spectrophotometric analysis of reaction products, and modelling of RfiA structure.
  
  
  RESULTS
  We describe a novel protein, RfiA, from Arthrobacter A3 that confers PC190723 resistance. RfiA is a PAP2 domain-containing polytopic transmembrane protein that can modify the fluoridated benzamide ring that is critical for high affinity binding of PC190723 with FtsZ.
  
  
  CONCLUSIONS
  RfiA-mediated modification of PC190723 is the first reported instance of resistance to this antibiotic involving a change to its structure. We predict that adoption of PC190723 or related benzamides as antimicrobials in clinical practice will lead to the acquisition by resistant pathogens of a gene encoding this subfamily of proteins.
authors: Key Laboratory of Extreme Environmental Microbial Resources & Engineering of Gansu Province, Lanzhou University, Lanzhou, Gansu, China.
authors: Ximing
authors: X
authors: Chen
authors: Binglin
authors: B
authors: Zhang
authors: Jianxi
authors: J
authors: Xiao
authors: Furong
authors: F
authors: Ju
authors: Shuyan
authors: S
authors: Li
authors: Cuiling
authors: C
authors: Ren
authors: Lizhe
authors: L
authors: An
authors: Tuo
authors: T
authors: Chen
authors: Guangxiu
authors: G
authors: Liu
authors: Paul
authors: P
authors: Facey
authors: Jonathan Gl
authors: JG
authors: Mullins
authors: Paul
authors: P
authors: Dyson
mesh_terms: D001173:Arthrobacter / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D001549:Benzamides / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D024881:Drug Resistance, Bacterial / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism*; D008826:Microbial Sensitivity Tests; D010802:Phylogeny; D011725:Pyridines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D001549:Benzamides; D003598:Cytoskeletal Proteins; C071525:FtsZ protein, Bacteria; D008565:Membrane Proteins; C531944:PC190723; D011725:Pyridines; D013844:Thiazoles; C037689:benzamide
keywords: FtsZ; antibiotic resistance; cell cytoskeleton; efflux; mechanisms of resistance