Phenotypes and gene expression profiles of Saccharopolyspora erythraea rifampicin-resistant (rif) mutants affected in erythromycin production

Carata, Elisabetta; Peano, Clelia; Tredici, Salvatore Maurizio; Ferrari, Francesco; Talà, Adelfia; Corti, Giorgio; Bicciato, Silvio; Bellis, Gianluca De; Alifano, Pietro

doi:10.1186/1475-2859-8-18

Cited by 47 publications

(54 citation statements)

References 69 publications

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“…The mechanism of action, however, remains to be clarified. The present method, together with other methods reported recently, 8,9,12,[22][23][24] may be useful for activating silent genes, eventually leading to the discovery of novel biologically active compounds. Figure 3 Comparative metabolic profiling of the culture extracts.…”

Section: Resultsmentioning

confidence: 81%

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

2010

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Genome sequencing projects have revealed many biosynthesis gene clusters for the production of as-yet unknown secondary metabolites, especially in actinomycetes. Here, we report that the rare earth elements, scandium and/or lanthanum, markedly activate, ranging from 2.5-to 12-fold, the expression of nine genes belonging to nine secondary metabolite-biosynthetic gene clusters of Streptomyces coelicolor A3(2) when added to the medium at low concentrations. HPLC analysis of ethyl acetateextractable metabolites indicated the detectability of several compounds only in the rare earth-treated cultures. This approach should facilitate discovery of new biologically active compounds and the study of secondary metabolite production.

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Section: Resultsmentioning

confidence: 81%

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

2010

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“…During the fermentation of Actinomycetes, high stirring speed damages the mycelium [18]. And the mycelium morphology of Actinomycetes plays an important role in polyketides production [19]. Our study found that electron acceptors can be provided without increasing stirring speed, which would damage the mycelium morphology of Actinomycetes.…”

Section: Discussionmentioning

confidence: 84%

Suitable extracellular oxidoreduction potential inhibit

et al. 2014

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Background: Polyketides, such as spinosad, are mainly synthesized in the stationary phase of the fermentation. The synthesis of these compounds requires many primary metabolites, such as acetyl-CoA, propinyl-CoA, NADPH, and succinyl-CoA. Their synthesis is also significantly influenced by NADH/NAD + . Rex is the sensor of NADH/NAD + redox state, whose structure is under the control of NADH/NAD + ratio. The structure of rex controls the expression of many NADH dehydrogenases genes and cytochrome bd genes. Intracellular redox state can be influenced by adding extracellular electron acceptor H 2 O 2 . The effect of extracellular oxidoreduction potential on spinosad production has not been studied. Although extracellular oxidoreduction potential is an important environment effect in polyketides production, it has always been overlooked. Thus, it is important to study the effect of extracellular oxidoreduction potential on Saccharopolyspora spinosa growth and spinosad production.

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“…Similarly, specific rpoB mutations in Bacillus subtilis lead to dramatic autoinduction of the antibiotic 3,3=-neotrehalosadiame (NTD), which wild-type strains do not produce (37). Remarkably, while only certain rpoB mutations are associated with gene upregulation in model organisms, the specific mutations most commonly associated with induced gene expression in nonmycobacterial organisms (13,35,37) align with mutations most commonly found in clinical rifampin-resistant M. tuberculosis strains (i.e., positions 445 and 450 in M. tuberculosis) (15,32,54,70,78). This suggests that those rpoB mutations that trigger upregulation of genes involved in biosynthesis of secondary metabolites are evolutionarily advantageous.…”

Section: Discussionmentioning

confidence: 99%

“…With this ranking, we then applied gene set enrichment analysis (GSEA) at the functional class level to identify significantly upregulated gene sets in the resistant strains (67). Because rpoB mutation appears to significantly upregulate genes specifically involved in biosynthesis of natural product/secondary metabolites in other organisms (13,34,35,37), we also used an automated approach to search the M. tuberculosis genome for gene clusters potentially associated with natural product biosynthesis (NP.searcher) (http://dna.sherman.lsi .umich.edu/; 49) and compared the expression of these gene clusters by mutants and wild-type M. tuberculosis using GSEA.…”

Section: Methodsmentioning

confidence: 99%

Upregulation of the Phthiocerol Dimycocerosate Biosynthetic Pathway by Rifampin-Resistant,rpoBMutant Mycobacterium tuberculosis

Bisson

Mehaffy²,

Broeckling

et al. 2012

J Bacteriol

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h Multidrug-resistant tuberculosis has emerged as a major threat to tuberculosis control. Phylogenetically related rifampin-resistant actinomycetes with mutations mapping to clinically dominant Mycobacterium tuberculosis mutations in the rpoB gene show upregulation of gene networks encoding secondary metabolites. We compared the expressed proteomes and metabolomes of two fully drug-susceptible clinical strains of M. tuberculosis (wild type) to those of their respective rifampin-resistant, rpoB mutant progeny strains with confirmed rifampin monoresistance following antitubercular therapy. Each of these strains was also used to infect gamma interferon-and lipopolysaccharide-activated murine J774A.1 macrophages to analyze transcriptional responses in a physiologically relevant model. Both rpoB mutants showed significant upregulation of the polyketide synthase genes ppsA-ppsE and drrA, which constitute an operon encoding multifunctional enzymes involved in the biosynthesis of phthiocerol dimycocerosate and other lipids in M. tuberculosis, but also of various secondary metabolites in related organisms, including antibiotics, such as erythromycin and rifamycins. ppsA (Rv2931), ppsB (Rv2932), and ppsC (Rv2933) were also found to be upregulated more than 10-fold in the Beijing rpoB mutant strain relative to its wild-type parent strain during infection of activated murine macrophages. In addition, metabolomics identified precursors of phthiocerol dimycocerosate, but not the intact molecule itself, in greater abundance in both rpoB mutant isolates. These data suggest that rpoB mutation in M. tuberculosis may trigger compensatory transcriptional changes in secondary metabolism genes analogous to those observed in related actinobacteria. These findings may assist in developing novel methods to diagnose and treat drug-resistant M. tuberculosis infections.A pproximately 9 million people develop active tuberculosis (TB) each year, resulting in nearly 2 million deaths annually (75). Recent progress controlling drug-susceptible TB has been made in many regions (50); however, drug resistance in Mycobacterium tuberculosis, including strains resistant to both first-line drugs, isoniazid and rifampin (multidrug-resistant [MDR] TB), has emerged as a threat to TB control worldwide (26, 65). Although international surveillance systems are inadequate, data from over 80 countries indicate that approximately 1 in 10 new cases of active TB have primary drug resistance (77), and MDR TB has been reported in essentially every country in which drug resistance has been studied (76). Treatment of MDR TB requires the use of costly and toxic second-line drugs for nearly 2 years and is associated with high rates of morbidity and mortality (65), which makes the spread of drug-resistant TB a major public health concern.Drug resistance in M. tuberculosis is due primarily to singlenucleotide polymorphisms in genes encoding key mycobacterial enzymes (6). The rpoB gene encodes the ␤-subunit of bacterial RNA polymerase, which is the target of rifampin (12...

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Phenotypes and gene expression profiles of Saccharopolyspora erythraea rifampicin-resistant (rif) mutants affected in erythromycin production

Cited by 47 publications

References 69 publications

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

Rare earth elements activate the secondary metabolite–biosynthetic gene clusters in Streptomyces coelicolor A3(2)

Suitable extracellular oxidoreduction potential inhibit

Upregulation of the Phthiocerol Dimycocerosate Biosynthetic Pathway by Rifampin-Resistant,rpoBMutant Mycobacterium tuberculosis

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