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Ferguson PP, Holloway WB, Setzer WN, et al. Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1. Antibiotics (Basel). 2016;5(2)doi: 10.3390/antibiotics5020016.
Ferguson, P. P., Holloway, W. B., Setzer, W. N., McFeeters, H., & McFeeters, R. L. (2016). Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1. Antibiotics (Basel, Switzerland), 5(2), . https://doi.org/10.3390/antibiotics5020016
Ferguson, Paul P, et al. "Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1." Antibiotics (Basel, Switzerland) vol. 5,2 (2016). doi: https://doi.org/10.3390/antibiotics5020016
Ferguson PP, Holloway WB, Setzer WN, McFeeters H, McFeeters RL. Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1. Antibiotics (Basel). 2016 May 10;5(2). doi: 10.3390/antibiotics5020016. PMID: 27171117; PMCID: PMC4929431.
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Antibiotics (Basel). 2016 May 10;5(2). doi: 10.3390/antibiotics5020016.

Small Molecule Docking Supports Broad and Narrow Spectrum Potential for the Inhibition of the Novel Antibiotic Target Bacterial Pth1.

Antibiotics (Basel, Switzerland)

Paul P Ferguson, W Blake Holloway, William N Setzer, Hana McFeeters, Robert L McFeeters

Affiliations

  1. Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. [email protected].
  2. Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. [email protected].
  3. Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. [email protected].
  4. Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. [email protected].
  5. Department of Chemistry, University of Alabama in Huntsville, 301 Sparkman Drive, Huntsville, AL 35899, USA. [email protected].

PMID: 27171117 PMCID: PMC4929431 DOI: 10.3390/antibiotics5020016

Abstract

Peptidyl-tRNA hydrolases (Pths) play ancillary yet essential roles in protein biosynthesis by recycling peptidyl-tRNA. In E. coli, inhibition of bacterial Pth1 leads to accumulation of peptidyl-tRNA, depletion of aminoacyl-tRNA, and cell death. Eukaryotes have multiple Pths and Pth1 knock out was shown to have no effect on viability in yeast. Thereby, bacterial Pth1 is a promising target for novel antibiotic development. With the abundance of Pth1 structural data, molecular docking was used for virtual screening of existing, commercially available antibiotics to map potential interactions with Pth enzymes. Overall, 83 compounds were docked to eight different bacterial Pth1 and three different Pth2 structures. A variety of compounds demonstrated favorable docking with Pths. Whereas, some compounds interacted favorably with all Pths (potential broad spectrum inhibition), more selective interactions were observed for Pth1 or Pth2 and even specificity for individual Pth1s. While the correlation between computational docking and experimentation still remains unknown, these findings support broad spectrum inhibition, but also point to the possibility of narrow spectrum Pth1 inhibition. Also suggested is that Pth1 can be distinguished from Pth2 by small molecule inhibitors. The findings support continued development of Pth1 as an antibiotic target.

Keywords: antibiotics; enzyme inhibitors; molecular docking; novel antibiotic target; peptidyl-tRNA hydrolase; protein biosynthesis inhibitor; tRNA

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