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Antibiotics (Basel). 2019 Apr 28;8(2). pii: E48. doi: 10.3390/antibiotics8020048.

Identification of Small Molecule Inhibitors of Staphylococcus aureus RnpA.

Author information

1
Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY 14642, USA. jennifer_colquhoun@urmc.rochester.edu.
2
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47906, USA. hal@purdue.edu.
3
Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY 14642, USA. amb462@pitt.edu.
4
Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY 14642, USA. brinkleymeyers@gmail.com.
5
Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN 47906, USA. dflaher@purdue.edu.
6
Purdue Institute of Inflammation, Immunology and Infectious Disease, Purdue University, West Lafayette, IN 47906, USA. dflaher@purdue.edu.
7
Purdue Institute for Drug Discovery, Purdue University, West Lafayette, IN 47906, USA. dflaher@purdue.edu.
8
Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY 14642, USA. paul_dunman@urmc.rochester.edu.

Abstract

Staphylococcus aureus RnpA is thought to be a unique dual functional antimicrobial target that is required for two essential cellular processes, precursor tRNA processing and messenger RNA degradation. Herein, we used a previously described whole cell-based mupirocin synergy assay to screen members of a 53,000 compound small molecule diversity library and simultaneously enrich for agents with cellular RnpA inhibitory activity. A medicinal chemistry-based campaign was launched to generate a preliminary structure activity relationship and guide early optimization of two novel chemical classes of RnpA inhibitors identified, phenylcarbamoyl cyclic thiophene and piperidinecarboxamide. Representatives of each chemical class displayed potent anti-staphylococcal activity, limited the protein's in vitro ptRNA processing and mRNA degradation activities, and exhibited favorable therapeutic indexes. The most potent piperidinecarboxamide RnpA inhibitor, JC2, displayed inhibition of cellular RnpA mRNA turnover, RnpA-depletion strain hypersusceptibility, and exhibited antimicrobial efficacy in a wax worm model of S. aureus infection. Taken together, these results establish that the whole cell screening assay used is amenable to identifying small molecule RnpA inhibitors within large chemical libraries and that the chemical classes identified here may represent progenitors of new classes of antimicrobials that target RnpA.

KEYWORDS:

RnpA; Staphylococcus aureus; mRNA degradation; mupirocin; tRNA processing

PMID:
31035380
DOI:
10.3390/antibiotics8020048
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