Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis

• DOI: 10.1371/journal.ppat.1001287
• Publication Date: 2011-02-11T00:12:49Z
• Authors: Patrick D. Olson; Lisa J. Kuechenme...; Kelsi L. Anderson; Sonja Daily; Karen E. Beenken; Christelle M. Roux; Michelle L. Reniere; Tami L. Lewis; William J. Weiss; Mark Pulse; Phung Nguyen; Jerry W. Simecka; John M. Morrison; Khalid Sayood; Oluwatoyin A. Asojo; Mark S. Smeltzer; Eric P. Skaar; Paul M. Dunman
• Keywords: 570; Staphylococcus aureus; QH301-705.5; Models, Biological; Ribonuclease P; Small Molecule Libraries; Mice; 03 medical and health sciences; Anti-Infective Agents; Vancomycin; 616; Animals; Humans; Computer Engineering; RNA, Messenger; Biology (General); RNA Processing, Post-Transcriptional; 0303 health sciences; Virulence; Hep G2 Cells; Electrical and Computer Engineering; RC581-607; Staphylococcal Infections; 3. Good health; Female; Immunologic diseases. Allergy; Research Article

Methicillin-resistant Staphylococcus aureus is estimated to cause more U.S. deaths annually than HIV/AIDS. The emergence of hypervirulent and multidrug-resistant strains has further amplified public health concern accentuated the need for new classes antibiotics. RNA degradation a required cellular process that could be exploited novel antimicrobial drug development. However, such discovery efforts have been hindered because components Gram-positive turnover machinery are incompletely defined. In current study we found essential S. protein, RnpA, catalyzes rRNA mRNA digestion in vitro. Exploiting this activity, high through-put secondary screening assays identified small molecule inhibitor RnpA-mediated vitro degradation. This agent was shown limit exhibited activity against predominant methicillin-resistant (MRSA) lineages circulating throughout U.S., vancomycin intermediate susceptible (VISA), resistant (VRSA) other bacterial pathogens with RnpA amino acid conservation. We also RnpA-inhibitor ameliorates disease systemic mouse infection model biofilm-associated aureus. Taken together, these findings indicate either alone, as component RNase P holoenzyme, and/or member elaborate complex, may play role provide proof principle catabolism-based therapy.