Self-resistance mechanism in Streptomyces peucetius: Overexpression of drrA, drrB and drrC for doxorubicin enhancement

Malla, Sailesh; Niraula, Narayan Prasad; Liou, Kwangkyoung; Sohng, Jae Kyung

doi:10.1016/j.micres.2009.04.002

Cited by 72 publications

(46 citation statements)

References 16 publications

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“…Matilla and colleagues (35) found that expression of PP2669 was strongly induced when KT2440 was present in the rhizosphere of plants, an environment where oxidative stress induced by antimicrobial secondary metabolites is relevant (7,64). PP2668 and PP2667 exhibited conserved sequences with respect to the DrrAB efflux system of Streptomyces that confers self-protection to producer strains against daunorubicin and doxorubicin, two anthracycline-type aromatic compounds (27,30,34). Thus, in KT2440, the efflux system consisting of PP2669/PP2668 and PP2667 may be involved in the direct efflux of chloramphenicol.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of Resistance to Chloramphenicol in Pseudomonas putida KT2440

Fernández

Conde

Torre

et al. 2012

Antimicrob Agents Chemother

102

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Pseudomonas putida KT2440 is a chloramphenicol-resistant bacterium that is able to grow in the presence of this antibiotic at a concentration of up to 25 g/ml. Transcriptomic analyses revealed that the expression profile of 102 genes changed in response to this concentration of chloramphenicol in the culture medium. The genes that showed altered expression include those involved in general metabolism, cellular stress response, gene regulation, efflux pump transporters, and protein biosynthesis. Analysis of a genome-wide collection of mutants showed that survival of a knockout mutant in the TtgABC resistance-nodulation-division (RND) efflux pump and mutants in the biosynthesis of pyrroloquinoline (PQQ) were compromised in the presence of chloramphenicol. The analysis also revealed that an ABC extrusion system (PP2669/PP2668/PP2667) and the AgmR regulator (PP2665) were needed for full resistance toward chloramphenicol. Transcriptional arrays revealed that AgmR controls the expression of the pqq genes and the operon encoding the ABC extrusion pump from the promoter upstream of open reading frame (ORF) PP2669.

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Section: Discussionmentioning

confidence: 99%

Mechanisms of Resistance to Chloramphenicol in Pseudomonas putida KT2440

Fernández

Conde

Torre

et al. 2012

Antimicrob Agents Chemother

102

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“…Until now, various self-protection mechanisms have been reported [15], and by enhancing these selfprotection mechanisms, the production of many antibiotics has been increased in various microorganisms. For example, Malla et al [14] overexpressed the resistance genes drrA, drrB and drrC in Streptomyces peucetius ATCC 27952, such that the recombinant strains produced more doxorubicin (DXR) than the parental strain. Indeed, there was a 2.2-fold increase in DXR in the drrAB mutant, a 5.1-fold increase in the drrC mutant and a 2.4-fold increase in the drrABC mutant.…”

Section: Discussionmentioning

confidence: 99%

“…After 6 days of incubation, mature spores were found on the surface of the SRI colony, but the SRI-B80 spores were malformed and immature. The onset of morphological differentiation generally coincides with the production of secondary metabolites and resistance genes are often co-regulated with these metabolites [14]. Indeed, spore formation is very closely related with the expression of resistance genes.…”

Section: Screening Of the High-productivity Mutantsmentioning

confidence: 99%

Introduction of Extra Copy of Oxytetracycline Resistance Gene otrB Enhances the Biosynthesis of Oxytetracycline in Streptomyces rimosus

Chu¹,

Zhen²,

Tang³

2012

J Bioproces Biotechniq

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The aromatic polyketide antibiotic oxytetracycline (OTC) is produced by Streptomyces rimosus as an important secondary metabolite. Enhancement of self-resistance is one effective way to improve antibiotic production in Streptomyces spp. In the present study, we aimed to improve the production of OTC by introducing extra copies of the OTC resistance genes, otrA and otrB, into the chromosome of the industrial strain of S. rimosus (SRI). First, otrA and otrB were cloned and ligated with pSET152 to generate the recombinant plasmids pSET152-otrA/otrB, the demethylated pSET152-otrA/otrB by Escherichia coli ET12567(pUZ8002) were then introduced into SRI to yield otrA/ otrB knock-in mutants: SRI-A (otrA) and SRI-B (otrB). Ten selected mutants and the parent SRI strain were cultured in shake flasks. Production of OTC was increased by 67% in one SRI-B mutant compared with the parent strain, suggesting that the enhancement of resistance gene otrB in the antibiotic producer is an effective way to improve OTC biosynthesis. However, introduction of extra copy of otrB could retard growth of mutant cells. Introduction of Extra Copy of Oxytetracycline Resistance Gene otrB Enhances the Biosynthesis of Oxytetracycline in Streptomyces rimosus

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“…producing daunorubicin and doxyrubicin [62] or netropsin (23) [63]. Similarly, intracellular accumulation can also be reduced through mutations in proteins involved…”

Section: Resistancementioning

confidence: 99%