1887

Abstract

Chromomycin A is an antitumour antibiotic that acts by inhibiting transcription and replication of DNA. The producer micro-organism subsp. is highly resistant to chromomycin A and to the structurally related compound mithramycin upon induction with chromomycin A. The biosynthetic gene cluster of chromomycin contains three genes involved in self-resistance to chromomycin in : and encode a type I ATP-binding cassette (ABC) transporter, and encodes a UvrA-like protein of ABC excision nuclease systems. These genes are linked in the chromosome, together with a gene encoding a transcriptional repressor (). Involvement of these genes in chromomycin resistance was determined through gene inactivation, and heterologous expression in . Inactivation of produced a chromomycin-sensitive low-producer strain, while inactivation of generated a high-chromomycin-producer strain, which was resistant to chromomycin, and also to mithramycin. Expression of either and , or , in generated strains with low chromomycin resistance; it was therefore necessary to co-express the three genes to achieve high levels of resistance. However, the CmrAB ABC transporter conferred a high level of resistance to the biosynthesis intermediate 4A,4E--dideacetyl-chromomycin A. A model is proposed for the biosynthesis of, and self-resistance to, chromomycin A in subsp.

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2007-09-01
2019-11-22
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