Pseudouridimycin: The First Nucleoside Analogue That Selectively Inhibits Bacterial RNA Polymerase

Chellat, Mathieu F.; Riedl, Rainer

doi:10.1002/anie.201708133

Cited by 26 publications

(19 citation statements)

References 10 publications

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“…In recent years, natural products have gained significant attention to overcome the gap in drug discovery and development due to their structure versatility and potential biological activity 4–8 . Majority of the antibiotics consumed at present are either the natural compounds or derivatives thereof, which were discovered from soil Actinomycetes in 1940–1960s i.e.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial properties of the novel bacterial isolate Paenibacilllus sp. SMB1 from a halo-alkaline lake in India

Singh

Kaur

Jangra

et al. 2019

Sci Rep

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Antibiotic-resistance is ever growing burden on our society for the past many years. Many synthetic chemistry approaches and rational drug-design have been unable to pace up and tackle this problem. Natural resources, more specifically, the microbial diversity, on the other hand, make a traditional and still the best platform to search for new chemical scaffolds and compounds. Here, we report the antimicrobial characteristics of novel bacterial isolate from a salt lake in India. We screened the bacterial isolates for their inhibitory activity against indicator bacteria and found that four novel species were able to prevent the growth of test strains studied in vitro . Further, we characterized one novel species (SMB1 T = SL4-2) using polyphasic taxonomic approaches and also purified the active ingredient from this bacterium. We successfully characterized the antimicrobial compound using mass spectroscopy and amino acid analysis. We also allocated two novel biosynthetic gene clusters for putative bacteriocins and one novel non-ribosomal peptide gene cluster in its whole genome. We concluded that the strain SMB1 T belonged to the genus Paenibacilllus with the pairwise sequence similarity of 98.67% with Paenibacillus tarimensis DSM 19409 T and we proposed the name Paenibacillus sambharensis sp. nov. The type strain is SMB1 T (=MTCC 12884 = KCTC 33895 T ).

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Section: Introductionmentioning

confidence: 99%

Antimicrobial properties of the novel bacterial isolate Paenibacilllus sp. SMB1 from a halo-alkaline lake in India

Singh

Kaur

Jangra

et al. 2019

Sci Rep

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“…Unsurprisingly, most of the research is still focused on improving existing antibiotics, expanding their spectrum, or combining them . Nevertheless, the discovery of the natural product pseudouridimycin in 2017 was quite significant and has proved not only that microbial extract screening is still a viable method of discovering novel antibiotics, but also that the pipeline is far from dry . In this manuscript, we will review some of the progress that has been made, both in the fight against antibiotic resistance and the discovery of new antibiotics.…”

Section: Introductionmentioning

confidence: 99%

A Structural View on Medicinal Chemistry Strategies against Drug Resistance

et al. 2019

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The natural phenomenon of drug resistance represents a generic impairment that hampers the benefits of drugs in all major clinical indications. Antibacterials and antifungals are affected as well as compounds for the treatment of cancer, viral infections or parasitic diseases. Despite the very diverse set of biological targets and organisms involved in the development of drug resistance, underlying molecular processes have been identified to understand the emergence of resistance and to overcome this detrimental mechanism. Detailed structural information of the root causes for drug resistance is nowadays frequently available to design next generation drugs anticipated to suffer less from resistance. This knowledge-based approach is a prerequisite in the fight against the inevitable occurrence of drug resistance to secure the achievements of medicinal chemistry in the future.

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“…Owing to the failure of synthetic chemistry approaches and re-discovery of already available antibiotics, it is, therefore, necessary to exploit the unique and underexplored microbial sources for new scaffolds or chemical compounds. Very recently, few reports have been published on the discovery of novel antibiotics from unculturable bacteria or bacteria from unusual niches (Ling et al, 2015; Zipperer et al, 2016; Chellat and Riedl, 2017; Hover et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Pseudomonas koreensis Recovered From Raw Yak Milk Synthesizes a β-Carboline Derivative With Antimicrobial Properties

et al. 2019

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Natural evolution in microbes exposed to antibiotics causes inevitable selection of resistant mutants. This turns out to be a vicious cycle which requires the continuous discovery of new and effective antibiotics. For the last six decades, we have been relying on semisynthetic derivatives of natural products discovered in “Golden Era” from microbes, especially Streptomyces sp. Low success rates of rational drug-design sparked a resurgence in the invention of novel natural products or scaffolds from untapped or uncommon microbial niches. Therefore, in this study, we examined the microbial diversity inhabiting the yak milk for their ability to produce antimicrobial compounds. We prepared the crude fermentation extracts of fifty isolates from yak milk and screened them against indicator strains for the inhibitory activity. Later, with the aid of gel filtration chromatography followed by reversed-phase HPLC, we isolated one antimicrobial compound Y5-P1 from the strain Y5 ( Pseudomonas koreensis ) which showed bioactivity against Gram-positive and Gram-negative bacteria. The compound was chemically characterized using HRMS, FTIR, and NMR spectroscopy and identified as 1-acetyl-9H-β-carboline-3-carboxylic acid. It showed minimum inhibitory activity (MIC) in the range of 62.5–250 μg /ml. The cytotoxicity results revealed that IC 50 against two mammalian cell lines i.e., HepG2 and HEK293T was 500 and 750 μg/ml, respectively. This is the first report on the production of this derivative of β-carboline by the microorganism. Also, the study enlightens the importance of microbes residing in uncommon environments or unexplored habitats in the discovery of a diverse array of natural products which could be designed further as drug candidates against highly resistant pathogens.

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Pseudouridimycin: The First Nucleoside Analogue That Selectively Inhibits Bacterial RNA Polymerase

Cited by 26 publications

References 10 publications

Antimicrobial properties of the novel bacterial isolate Paenibacilllus sp. SMB1 from a halo-alkaline lake in India

Antimicrobial properties of the novel bacterial isolate Paenibacilllus sp. SMB1 from a halo-alkaline lake in India

A Structural View on Medicinal Chemistry Strategies against Drug Resistance

Pseudomonas koreensis Recovered From Raw Yak Milk Synthesizes a β-Carboline Derivative With Antimicrobial Properties

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