Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12

Hosaka, Takeshi; Ohnishi‐Kameyama, Mayumi; Muramatsu, Hideyuki; Murakami, Kiyoshi; Tsurumi, Yasuhisa; Kodani, Shinya; Yoshida, Mitsuru; Fujie, Akihiko; Ochi, Kozo

doi:10.1038/nbt.1538

Cited by 216 publications

(193 citation statements)

References 15 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%

“…12,17 The activation of silent genes by generating rpoB H437D or rpoB H437L mutations in Streptomyces sp. 631689 was attributed, at least in part, to the increased affinity of the mutant RNA polymerase for promoters.…”

Section: Effects Of Scandium and Lanthanum On Transcription Of Secondmentioning

confidence: 99%

“…These studies showed that mutations in ribosomal proteins and/ or RNA polymerase alter bacterial gene expression, eventually leading to the discovery of novel antibiotics. 12 More recently, during the course of studying the effects of rare earth elements on bacterial physiology, we found that rare earths can elicit bacterial capabilities, and thus exert marked effects on secondary metabolism in streptomycetes, the typical soil microorganisms that often produce antibiotics. 13 Rare earth is a general term for 17 elements that include scandium (Sc), yttrium (Y) and the lanthanides (15 elements from lanthanum (La) to lutetium (Lu)).…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Effects Of Scandium and Lanthanum On Transcription Of Secondmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

2010

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“…For this, different expression strains have been developed to facilitate gene cluster expression and metabolite detection. For instance, the model organism S. coelicolor has been genetically engineered in a manner that positively affects antibiotic production in general (by altered RNA polymerase and ribosome) (Hosaka et al ., 2009) and in addition alleviates the detection of antibiotic production (by inactivated active secondary metabolite gene clusters ( ∆act ∆red ∆cpk ∆cda )) (Gomez‐Escribano and Bibb, 2012). Heterologous expression of antibiotic gene clusters has been a challenge for a long time because cluster sizes can easily reach more than 100 kb, which makes them difficult to clone.…”

Section: Novel Approaches For Drug Discoverymentioning

confidence: 99%

Antibiotic drug discovery

Wohlleben

Mast

Stegmann

et al. 2016

Microbial Biotechnology

138

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SummaryDue to the threat posed by the increase of highly resistant pathogenic bacteria, there is an urgent need for new antibiotics; all the more so since in the last 20 years, the approval for new antibacterial agents had decreased. The field of natural product discovery has undergone a tremendous development over the past few years. This has been the consequence of several new and revolutionizing drug discovery and development techniques, which is initiating a ‘New Age of Antibiotic Discovery’. In this review, we concentrate on the most significant discovery approaches during the last and present years and comment on the challenges facing the community in the coming years.

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“…This in turn revealed that the previously identified molecule pulvomycin inhibits the growth of several highly resistant pathogenic bacteria. It is our hope that screening engineered streptomycetes against both antibioticsensitive and -resistant target strains, along with innovations from other laboratories, 21 will help to fuel a much needed renaissance in antibacterial discovery.…”

Section: Discussionmentioning

confidence: 99%

Induction of antimicrobial activities in heterologous streptomycetes using alleles of the Streptomyces coelicolor gene absA1

et al. 2010

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The bacterial genus Streptomyces is endowed with a remarkable secondary metabolism that generates an enormous number of bioactive small molecules. Many of these genetically encoded small molecules are used as antibiotics, anticancer agents and as other clinically relevant therapeutics. The rise of resistant pathogens has led to calls for renewed efforts to identify antimicrobial activities, including expanded screening of streptomycetes. Indeed, it is known that most strains encode 420 secondary metabolites and that many, perhaps most of these, have not been considered for their possible therapeutic use. One roadblock is that many strains do not express their secondary metabolic gene clusters efficiently under laboratory conditions. As one approach to this problem, we have used alleles of a pleiotropic regulator of secondary metabolism from Streptomyces coelicolor to activate secondary biosynthetic gene clusters in heterologous streptomycetes. In one case, we demonstrate the activation of pulvomycin production in S. flavopersicus, a metabolite not previously attributed to this species. We find that the absA1-engineered strains produced sufficient material for purification and characterization. As a result, we identified new, broad-spectrum antimicrobial activities for pulvomycin, including a potent antimicrobial activity against highly antibioticresistant Gram-negative and Gram-positive pathogens.

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Antibacterial discovery in actinomycetes strains with mutations in RNA polymerase or ribosomal protein S12

Cited by 216 publications

References 15 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)

Antibiotic drug discovery

Induction of antimicrobial activities in heterologous streptomycetes using alleles of the Streptomyces coelicolor gene absA1

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