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Antimicrob Agents Chemother. 2015 Apr;59(4):2016-28. doi: 10.1128/AAC.04352-14. Epub 2015 Jan 20.

Small-molecule inhibitors of Staphylococcus aureus RnpA-mediated RNA turnover and tRNA processing.

Author information

1
Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry Rochester, New York, USA.
2
Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania, USA.
3
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry Rochester, New York, USA.
4
Moulder Center for Drug Discovery Research, Temple University, Philadelphia, Pennsylvania, USA wayne.childers@temple.edu paul_dunman@urmc.rochester.edu.
5
Department of Microbiology and Immunology, University of Rochester School of Medicine and Dentistry Rochester, New York, USA wayne.childers@temple.edu paul_dunman@urmc.rochester.edu.

Abstract

New agents are urgently needed for the therapeutic treatment of Staphylococcus aureus infections. In that regard, S. aureus RNase RnpA may represent a promising novel dual-function antimicrobial target that participates in two essential cellular processes, RNA degradation and tRNA maturation. Accordingly, we previously used a high-throughput screen to identify small-molecule inhibitors of the RNA-degrading activity of the enzyme and showed that the RnpA inhibitor RNPA1000 is an attractive antimicrobial development candidate. In this study, we used a series of in vitro and cellular assays to characterize a second RnpA inhibitor, RNPA2000, which was identified in our initial screening campaign and is structurally distinct from RNPA1000. In doing so, it was found that S. aureus RnpA does indeed participate in 5'-precursor tRNA processing, as was previously hypothesized. Further, we show that RNPA2000 is a bactericidal agent that inhibits both RnpA-associated RNA degradation and tRNA maturation activities both in vitro and within S. aureus. The compound appears to display specificity for RnpA, as it did not significantly affect the in vitro activities of unrelated bacterial or eukaryotic ribonucleases and did not display measurable human cytotoxicity. Finally, we show that RNPA2000 exhibits antimicrobial activity and inhibits tRNA processing in efflux-deficient Gram-negative pathogens. Taken together, these data support the targeting of RnpA for antimicrobial development purposes, establish that small-molecule inhibitors of both of the functions of the enzyme can be identified, and lend evidence that RnpA inhibitors may have broad-spectrum antimicrobial activities.

PMID:
25605356
PMCID:
PMC4356807
DOI:
10.1128/AAC.04352-14
[Indexed for MEDLINE]
Free PMC Article

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