Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

Kirsch, Sarah; Haeckl, F. P. Jake; Müller, Rolf

doi:10.1039/d1np00067e

Cited by 27 publications

(20 citation statements)

References 496 publications

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“…Our lab has previously reported the structure and activity of lasso peptides ubonodin and citrocin, which were shown to be potent inhibitors of RNAP, similar to the lasso peptides MccJ25, klebsidin, and acinetodin (Figure B). ,,− Due to the presence of the conserved Tyr residues, we predicted that cloacaenodin may also function by inhibiting RNAP. However, the C-terminal amino acid in cloacaenodin is serine, differing from the conserved glycine seen in other RNAP-targeting lasso peptides (Figure B).…”

Section: Resultsmentioning

confidence: 72%

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

et al. 2022

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Using genome mining and heterologous expression, we report the discovery and production of a new antimicrobial lasso peptide from species related to the Enterobacter cloacae complex. Using NMR and mass spectrometric analysis, we show that this lasso peptide, named cloacaenodin, employs a threaded lasso fold which imparts proteolytic resistance that its unthreaded counterpart lacks. Cloacaenodin has selective, low micromolar, antimicrobial activity against species related to the E. cloacae complex, including species implicated in nosocomial infections and against clinical isolates of carbapenem-resistant Enterobacterales. We further used site-directed mutagenesis to probe the importance of specific residues to the peptide's biosynthesis, stability, and bioactivity.

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Section: Resultsmentioning

confidence: 72%

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

et al. 2022

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“…On the other hand, topoisomerase II (DNA gyrase) is also implicated in DNA replication and transcription processes and has an imperative role characterized by its ability to catalyze the unwinding of supercoiled DNA strands [ 101 ]. These imperative enzymes constitute attractive and validated targets for antibacterial agents [ 102 ]. Molecular docking simulation results are elucidated by ( Table 4 ).…”

Section: Resultsmentioning

confidence: 99%

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

Akermi

Smaoui

Fourati

et al. 2022

BioMed Research International

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Questions have been raised apropos the emerging problem of microbial resistance, which may pose a great hazard to the human health. Among biosafe compounds are essential oils which captured consumer draw due to their multifunctional properties compared to chemical medication drugs. Here, we examined the chemical profile and the mechanism(s) of action of the Thymus vulgaris essential oil (TVEO) against a Gram-negative bacterium Salmonella enterica Typhimurium ATTCC 10028 (S. enterica Typhimurium ATTCC 10028) and two Gram-positive bacteria Staphyloccocus aureus ATCC 6538 (S. aureus ATCC 6538) and Listeria monocytogenes ATCC 19117 (L. monocytogenes ATCC 19117). Findings showed that TVEO was principally composed of thymol, o-cymene, and γ-terpinene with 47.44, 16.55, and 7.80%, respectively. Molecular docking simulations stipulated that thymol and β-sesquiphellandrene (a minor compound at 1.37%) could target multiple bacterial pathways including topoisomerase II and DNA and RNA polymerases of the three tested bacteria. This result pointed plausible impairments of the pathogenic bacteria cell replication and transcription processes. Through computational approach, the VEGA quantitative structure–activity relationship (QSAR) model, we revealed that among twenty-six TVEO compounds, sixteen had no toxic effects and could be safe for human consumption as compared to the Food and Drug Administration (FDA) approved drugs (ciprofloxacin and rifamycin SV). Assessed by the SwissADME server, the pharmacokinetic profile of all identified TVEO compounds define their absorption, distribution, metabolism, and excretion (ADME) properties and were assessed. In order to predict their biological activity spectrum based on their chemical structure, all TVEO compounds were subjected to PASS (Prediction of Activity Spectra for Substances) online tool. Results indicated that the tested compounds could have multiple biological activities and various enzymatic targets. Findings of our study support that identified compounds of TVEO can be a safe and effective alternative to synthetic drugs and can easily combats hazardous multidrug-resistant bacteria.

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“…Since their introduction in the 1940s, antibiotics have been heavily applied to treat infectious diseases. After the “Golden Age” of antibiotics, semisynthetic and chemically modified antibiotics have been deemed as the bright way to develop new antibiotics [ 33 , 34 , 35 , 36 , 37 ]. However, these innovative compounds cannot address the antibiotic-resistant issues as bacteria could rapidly acquire tolerance after a period of gene response.…”

Section: Supramolecular Self-assembly Of Antibioticsmentioning

confidence: 99%

Combatting Antibiotic Resistance Using Supramolecular Assemblies

Guo

Yuan-yuan

et al. 2022

Pharmaceuticals

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Antibiotic resistance has posed a great threat to human health. The emergence of antibiotic resistance has always outpaced the development of new antibiotics, and the investment in the development of new antibiotics is diminishing. Supramolecular self-assembly of the conventional antibacterial agents has been proved to be a promising and versatile strategy to tackle the serious problem of antibiotic resistance. In this review, the recent development of antibacterial agents based on supramolecular self-assembly strategies will be introduced.

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Beyond the approved: target sites and inhibitors of bacterial RNA polymerase from bacteria and fungi

Abstract: Bacterial RNA polymerase is an attractive target for the development of antibacterial therapeutics. We review the mode of action of approved compounds and highlight additional emerging target sites inhibited primarily by microbial natural products.

Cited by 27 publications

References 496 publications

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

Cloacaenodin, an Antimicrobial Lasso Peptide with Activity against Enterobacter

In-Depth Study of Thymus vulgaris Essential Oil: Towards Understanding the Antibacterial Target Mechanism and Toxicological and Pharmacological Aspects

Combatting Antibiotic Resistance Using Supramolecular Assemblies

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