title: Resistance to trifluoroperazine, a calmodulin inhibitor, maps to the fabD locus in Escherichia coli.
abstract: A mutant, tfpA1, resistant to the calmodulin inhibitor trifluoroperazine (TFP) at 30 degrees C, was isolated in Escherichia coli. The mutant showed a reduced growth rate at 30 degrees C and was temperature sensitive (ts) at 42 degrees C for growth, forming short filaments. The mutation was mapped to the 24 min region of the chromosome and the gene was cloned by complementation of the ts defect. Subsequent subcloning, complementation analysis, marker rescue mapping and sequencing, identified tfpA as fabD, encoding the 35 kDa, malonyl-coenzyme A transacylase (MCT) enzyme, required for the initial step in the elongation cycle for fatty acid biosynthesis. Resistance to TFP may result from altered permeability of the cell envelope, although the mutant remained sensitive to other calmodulin inhibitors and to other antibacterial agents. Alternatively, resistance may be more indirect, resulting from alterations in intracellular Ca++ levels which affect the activity of the TFP target in some way.
authors.affiliation: Insitut de Génétique et Microbiologie, CNRS URA 1354, Université Paris XI, Orsay, France.
authors.forename: N
authors.initials: N
authors.lastname: Bouquin
authors.forename: M
authors.initials: M
authors.lastname: Tempête
authors.forename: I B
authors.initials: IB
authors.lastname: Holland
authors.forename: S J
authors.initials: SJ
authors.lastname: Séror
mesh_terms: D051080:Acyl-Carrier Protein S-Malonyltransferase; D000217:Acyltransferases / Q000235:genetics*; D001426:Bacterial Proteins / Q000032:analysis / Q000737:chemistry; D001483:Base Sequence; D002147:Calmodulin / Q000037:antagonists & inhibitors; D002462:Cell Membrane / Q000378:metabolism; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004352:Drug Resistance, Microbial / Q000235:genetics*; D004926:Escherichia coli / Q000187:drug effects / Q000235:genetics*; D029968:Escherichia coli Proteins; D054889:Fatty Acid Synthase, Type II; D005227:Fatty Acids / Q000096:biosynthesis; D005798:Genes, Bacterial / Q000235:genetics*; D005816:Genetic Complementation Test; D008969:Molecular Sequence Data; D008970:Molecular Weight; D009154:Mutation / Q000235:genetics; D017422:Sequence Analysis, DNA; D013696:Temperature; D014268:Trifluoperazine / Q000494:pharmacology*
chemical_list: D001426:Bacterial Proteins; D002147:Calmodulin; D029968:Escherichia coli Proteins; D005227:Fatty Acids; D014268:Trifluoperazine; D000217:Acyltransferases; D051080:Acyl-Carrier Protein S-Malonyltransferase; C494968:fabD protein, E coli; D054889:Fatty Acid Synthase, Type II