An ABC transporter is essential for resistance to the antitumor agent mithramycin in the producerStreptomyces argillaceus View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

1996-07

AUTHORS

E. Fernández, F. Lombó, C. Méndez, J. A. Salas

ABSTRACT

Mithramycin is an antitumor antibiotic synthesized by Streptomyces argillaceus. This producer strain is highly resistant in vivo to mithramycin (MIC 100 micrograms/ml) but sensitive to the related drugs chromomycin and olivomycin (MIC 10 micrograms/ml). From a genomic library of S. argillaceus DNA two cosmid clones were isolated which confer a high level of resistance to mithramycin on S. albus. The resistance genes were mapped by subcloning to a 3.9-kb PstI-PvuII fragment. DNA sequence analysis of this fragment revealed one incomplete and three complete open reading frames. Subcloning experiments demonstrated that resistance to mithramycin is mediated by the genes mtrA and mtrB. The mtrA gene can potentially encode an ATP-binding protein of the ABC transporter superfamily, containing one nucleotide-binding domain and showing similarity with other ABC transporters involved in resistance to daunorubicin, oleandomycin and tetronasin in their respective producer strains. The mtrB gene codes for an integral membrane protein with six putative transmembrane helices. A mithramycin-sensitive mutant was generated in a gene replacement experiment by disrupting the mtrA gene, thus demonstrating that the system encoded by the mtrAB genes is essential for conferring resistance to mithramycin in S. argillaceus. More... »

PAGES

692-698

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/bf02174118

DOI

http://dx.doi.org/10.1007/bf02174118

DIMENSIONS

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PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/8757400


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52 schema:description Mithramycin is an antitumor antibiotic synthesized by Streptomyces argillaceus. This producer strain is highly resistant in vivo to mithramycin (MIC 100 micrograms/ml) but sensitive to the related drugs chromomycin and olivomycin (MIC 10 micrograms/ml). From a genomic library of S. argillaceus DNA two cosmid clones were isolated which confer a high level of resistance to mithramycin on S. albus. The resistance genes were mapped by subcloning to a 3.9-kb PstI-PvuII fragment. DNA sequence analysis of this fragment revealed one incomplete and three complete open reading frames. Subcloning experiments demonstrated that resistance to mithramycin is mediated by the genes mtrA and mtrB. The mtrA gene can potentially encode an ATP-binding protein of the ABC transporter superfamily, containing one nucleotide-binding domain and showing similarity with other ABC transporters involved in resistance to daunorubicin, oleandomycin and tetronasin in their respective producer strains. The mtrB gene codes for an integral membrane protein with six putative transmembrane helices. A mithramycin-sensitive mutant was generated in a gene replacement experiment by disrupting the mtrA gene, thus demonstrating that the system encoded by the mtrAB genes is essential for conferring resistance to mithramycin in S. argillaceus.
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