Mechanisms of antibiotics inhibiting bacterial RNA polymerase

Mosaei, Hamed; Harbottle, John

doi:10.1042/bst20180499

Cited by 41 publications

(39 citation statements)

References 82 publications

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“…Prokaryotic RNAP widely differs from eukaryotic RNAP and therefore renders this enzyme a convenient target for antibiotics as they specifically act on bacterial RNAP. During initiation of the transcription, the σ ‐factor needs to bind to the core enzyme to enable binding of the DNA‐strand . The promoter specific σ ‐factor consist of separate domains 1–4.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Dorst

Gademann

2020

Helvetica Chimica Acta

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Fidaxomicin (1, lipiarmycin A3, clostomicin B1, tiacumicin B) constitutes a glycosylated 18-membered macrolactone and is a natural product isolated from various soil bacteria. Since 2011, fidaxomicin is a marketed antibiotic for the treatment of intestine infections caused by C. difficile in the clinic. Its promising in vitro antibacterial properties against resistant S. aureus and M. tuberculosis continue to attract interest. This review article describes the early history of the antibiotic fidaxomicin and highlights recent advances in the field, such as the elucidation of its mode of action and biosynthesis, as well as known derivatives. Furthermore, different synthetic strategies towards the total synthesis of fidaxomicin are summarized.

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Section: Mechanism Of Actionmentioning

confidence: 99%

“…Further mode of actions of antibiotics known to inhibit RNAP (not marketed drugs) include disruption of holoenzyme assembly, blocking conformational dynamics required for nucleotide addition and blocking nucleoside triphosphate (NTP) uptake …”

Section: Mechanism Of Actionmentioning

confidence: 99%

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Dorst

Gademann

2020

Helvetica Chimica Acta

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“…Subsequent efforts to improve the GE23077 antibacterial activity and extend its antimicrobial spectrum by chemical modifications allowing its penetration into whole cells were unsuccessful; the patent was thus left aside [29]. Due to its specific and selective mode of action, we recently assisted with renewed interest in this bacterial RNA polymerase inhibitor that does not show cross-resistance with rifamycins [30, 31]. Since the GE23077-producing strain (purchased from DSMZ and coded as VA325 in our University strain collection) remained poorly characterized taxonomically, in the present study we describe its polyphasic taxonomic analysis and propose that it represents a novel species of the genus Actinomadura , which has been deposited as NRRL B-65521 T (=LMG 31258 T =DSM 109019 T ).…”

Section: Full-textmentioning

confidence: 99%

Description of the bacterial RNA polymerase inhibitor GE23077-producer Actinomadura sp. NRRL B-65521T as Actinomadura lepetitiana sp. nov.

Dalmastri

Gastaldo

Berini

et al. 2020

International Journal of Systematic and Evolutionary Microbiology

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The filamentous actinomycete that produces the antibiotic GE23077 was isolated by the Lepetit Research Group from a soil sample collected in Thailand, and it was classified as a member of the genus Actinomadura on the basis of its morphology and cell-wall composition. Phylogenetic analysis based on 16S rRNA gene sequences indicated that this strain formed a distinct monophyletic line within the genus Actinomadura, and it was most closely related to Actinomadura bangladeshensis DSM 45347T (99.31 % similarity) and Actinomadura mexicana DSM 44485T (98.94 %). The GE23077-producing strain formed an extensively branched, non-fragmented vegetative mycelium; no pseudosporangia were formed and the arthrospores were organized in slightly twisted chains. The cell wall contained meso-2,6-diaminopimelic acid and the diagnostic sugar was madurose. The predominant menaquinone was MK-9(H6), with minor amounts of MK-9(H8) and MK-9(H4). The diagnostic phospholipids were phosphatidylinositol and diphosphatidylglycerol. The major cellular fatty acids were C16 : 0 and tuberculostearic acid (10-methyloctadecanoic acid), followed by minor amounts of C18:1ω9c, C16:1ω7c and 10-methylheptadecanoic acid. The genomic DNA G+C content was 71.77 mol%. Significant differences in the morphological, chemotaxonomic and biochemical data, and the low DNA–DNA relatedness between the GE23077-producing strain and closely related type strains clearly demonstrate that it represents a novel species of the genus Actinomadura , for which the name Actinomadura lepetitiana sp. nov. is proposed. The type strain is NRRL B-65521T(=LMG 31258T=DSM 109019T).

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“…Multi-subunit RNAPs initiate the transcription of DNA through a process that is central to the regulation of gene expression in all domains of life [1][2][3]. A quantitative understanding of this process is vital in outlining the bacterial regulatory network and its dynamic response to environmental changes, identifying and characterizing new targets for antibacterial drug design [4], and developing baseline kinetic mechanisms of transcription initiation to maximize the information gained from genome-wide comparison experiments [5].…”

Section: Introductionmentioning

confidence: 99%

Mechanism of upstream promoter element stimulation of transcription at a ribosomal RNA promoter determined by single-molecule imaging

Jp¹,

Friedman²,

Gelles³

2020

Preprint

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DNA elements upstream of transcription promoters play a role in regulating transcription initiation in all organisms. In bacteria, upstream A-T rich sequences called UP elements can stimulate transcription through contact with the α subunit C-terminal domain (αCTD) of core RNA polymerase (RNAP), but the kinetic mechanisms by which they do so remain unclear. We investigated the role of the UP element in stimulating initiation from the strong E. coli 16s rRNA promoter using single-molecule fluorescence microscopy to visualize σ 70 RNAP holoenzyme binding and the formation nascent RNA by oligonucleotide probe hybridization on individual DNA molecules containing the rrnB P1 promoter. By directly detecting initial binding of σ 70 RNAP to promoter and monitoring the lifetimes of promoter-polymerase complexes, the experiments reveal the kinetic mechanism of polymerase recruitment to the promoter and the subsequent conformational change that stabilizes binding. The presence of UP stimulated the rate of initial binding of polymerase to promoter by at least six-fold, and this stimulation was fully sufficient to account for the increase in initiation rate by UP. Thus, UP likely functions at this strong promoter simply by acting as a binding target for the rapidly reorienting αCTD domain tethered to the core polymerase. In contrast, there were only minor effects of UP on the measured rates of the conformational change or the dissociation rates of the initial σ 70 RNAP promoter complexes. These studies define a paradigmatic kinetic mechanism for stimulation of transcription initiation by direct αCTD-DNA interactions. This mechanism can serve as a building block of more complex regulatory architectures in which αCTD promotes transcription through interactions with both DNA and protein activators.

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Mechanisms of antibiotics inhibiting bacterial RNA polymerase

Cited by 41 publications

References 82 publications

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Chemistry and Biology of the Clinically Used Macrolactone Antibiotic Fidaxomicin

Description of the bacterial RNA polymerase inhibitor GE23077-producer Actinomadura sp. NRRL B-65521T as Actinomadura lepetitiana sp. nov.

Mechanism of upstream promoter element stimulation of transcription at a ribosomal RNA promoter determined by single-molecule imaging

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