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Sökning: WFRF:(Parajuli Narayan Prasad 1989 )

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1.
  • Parajuli, Narayan Prasad, 1989-, et al. (författare)
  • Antibiotic thermorubin tethers ribosomal subunits and impedes A-site interactions to perturb protein synthesis in bacteria
  • 2023
  • Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
  • Tidskriftsartikel (refereegranskat)abstract
    • Thermorubin (THB) is a long-known broad-spectrum ribosome-targeting antibiotic, but the molecular mechanism of its action was unclear. Here, our precise fast-kinetics assays in a reconstituted Escherichia coli translation system and 1.96 Å resolution cryo-EM structure of THB-bound 70S ribosome with mRNA and initiator tRNA, independently suggest that THB binding at the intersubunit bridge B2a near decoding center of the ribosome interferes with the binding of A-site substrates aminoacyl-tRNAs and class-I release factors, thereby inhibiting elongation and termination steps of bacterial translation. Furthermore, THB acts as an anti-dissociation agent that tethers the ribosomal subunits and blocks ribosome recycling, subsequently reducing the pool of active ribosomes. Our results show that THB does not inhibit translation initiation as proposed earlier and provide a complete mechanism of how THB perturbs bacterial protein synthesis. This in-depth characterization will hopefully spur efforts toward the design of THB analogs with improved solubility and effectivity against multidrug-resistant bacteria.
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2.
  • Parajuli, Narayan Prasad, 1989- (författare)
  • Molecular Interplay of Antibiotics on the Bacterial Ribosome
  • 2022
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Inhibition of protein synthesis is one of the most common modes of action for medically useful antibiotics. This thesis presents the mechanistic studies of two chemically distinct classes of antibiotics that target bacterial ribosomes –aminoglycosides and thermorubin. Arbekacin (ABK) and amikacin (AMK) are two new-generation semisynthetic aminoglycosides (AGAs) that were developed to overcome enzyme-mediated AGA resistance in bacteria. Our results demonstrate that these two antibiotics induce potent inhibitory effects on various phases of bacterial protein synthesis. The binding of ABK stalls elongating ribosomes to a state that is unfavorable for elongation factor-G (EF-G) binding, which drastically prolongs the time for translocation from ~50 milliseconds to at least 2 seconds. ABK also abolishes the accuracy of mRNA decoding and inhibits peptide release. The results of in vitro fast kinetics and structures of ABK and AMK-bound 70S ribosomes reveal that in addition to canonical binding at h44 of 16S rRNA, appended amino-hydroxy butyryl (AHB) moiety of ABK and AMK secures extra interactions at the binding pocket and provides long dwelling-time on the translating ribosome. Moreover, AMK binds at the large subunit of ribosome proximal to the 3'CCA-end of the tRNA in the P-site and inhibits the release factor-mediated peptide release. Our data suggest that AGA impose bacteriostatic effects mainly by inhibiting translocation, while they become bactericidal in combination with decoding errors. We have further characterized the molecular mechanism of action of the antibiotic thermorubin (THB) using in vitro fast kinetics and cryo-EM. We found that THB impedes elongation, termination, and ribosome recycling phases of translation. THB does so by binding to the intersubunit bridge B2a and extruding C1914 of H69 of 23S rRNA that interferes with the interactions of A-site substrates including aminoacyl-tRNAs, class-I release factors, and ribosome recycling factor. We also found that THB acts as an anti-dissociation agent that tethers the ribosomal subunits and blocks ribosome recycling, subsequently reducing the pool of active ribosomes. These studies altogether suggest that in-depth characterization of antibiotic action provides important clues that hopefully aid in the development of new antibiotics to fight against looming antibiotic resistance.
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