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

Authors

Patrick D. Olson, University of Nebraska Medical Center
Lisa J. Kuechenmeister, University of Nebraska Medical Center
Kelsi L. Anderson, University of Nebraska Medical Center
Sonja Daily, University of Arkansas for Medical Sciences
Karen E. Beenken, University of Arkansas for Medical Sciences
Christelle M. Roux, University of Nebraska Medical Center
Michelle L. Reniere, Vanderbilt University Medical Center
Tami L. Lewis, University of Nebraska Medical Center
William J, Weiss, University of North Texas Health Science Center
Mark Pulse, University of North Texas Health Science Center
Phung Nguyen, University of North Texas Health Science Center
Jerry W. Simecka, University of North Texas Health Science Center
John M. Morrison, University of Nebraska Medical Center
Khalid Sayood, University of Nebraska-LincolnFollow
Oluwatoyin A. Asojo, University of Nebraska Medical Center
Mark S. Smeltzer, University of Arkansas for Medical Sciences
Eric P. Skaar, Vanderbilt University Medical Center
Paul M. Dunman, University of RochesterFollow

Document Type

Article

Date of this Version

2011

Citation

Olson PD, Kuechenmeister LJ, Anderson KL, Daily S, Beenken KE, et al. (2011) Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis. PLoS Pathog 7(2): e1001287. doi:10.1371/journal.ppat.1001287

Comments

This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose.

Abstract

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