Small Molecule Inhibitors of Staphylococcus aureus RnpA Alter Cellular mRNA Turnover, Exhibit Antimicrobial Activity, and Attenuate Pathogenesis
| Autor: | Sonja T. Daily, Michelle L. Reniere, Lisa J. Kuechenmeister, Patrick D. Olson, Karen E. Beenken, Tami L. Lewis, Jerry W. Simecka, Oluwatoyin A. Asojo, William J. Weiss, Christelle M. Roux, Mark Pulse, Phung Nguyen, Eric P. Skaar, John M. Morrison, Paul M. Dunman, Khalid Sayood, Mark S. Smeltzer, Kelsi L. Anderson |
|---|---|
| Rok vydání: | 2011 |
| Předmět: |
medicine.disease_cause
Infectious Diseases/Bacterial Infections Mice Anti-Infective Agents Biology (General) RNA Processing Post-Transcriptional 0303 health sciences Virulence Hep G2 Cells Staphylococcal Infections Antimicrobial 3. Good health Antisense RNA Infectious Diseases Staphylococcus aureus Vancomycin Female Molecular Biology/mRNA Stability Research Article medicine.drug QH301-705.5 RNase P Immunology Biology Staphylococcal infections Models Biological Microbiology Ribonuclease P Small Molecule Libraries Microbiology/Applied Microbiology 03 medical and health sciences Virology Genetics medicine Animals Humans RNA Messenger Molecular Biology 030304 developmental biology Infectious Diseases/Antimicrobials and Drug Resistance 030306 microbiology RNA RC581-607 medicine.disease Methicillin-resistant Staphylococcus aureus Molecular Biology/Post-Translational Regulation of Gene Expression Parasitology Immunologic diseases. Allergy |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 7, Iss 2, p e1001287 (2011) |
| ISSN: | 1553-7374 |
| DOI: | 10.1371/journal.ppat.1001287 |
| Popis: | 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. Author Summary The last decade has witnessed a mass downsizing in pharmaceutical antibiotic drug discovery initiatives. This has posed a major healthcare issue that will likely worsen with time; antibiotic resistant bacteria continue to emerge while advances in new therapeutic options languish. In the current body of work, we show that agents that limit bacterial RNA turnover have potential as a new class of antibiotics. More specifically, our findings indicate the essential bacterial protein, RnpA, exhibits in vitro ribonuclease activity and either alone and/or as a member of the RNase P holoenzyme, may contribute to the RNA degradation properties of Staphylococcus aureus, a predominant cause of hospital and community bacterial infections. Accordingly, using high throughput screening we identified small molecule inhibitors of RnpA's in vitro RNA degradation activity. One of these agents, RNPA1000, was shown to limit S. aureus mRNA turnover and growth. RNPA1000 also limited growth of other important Gram-positive bacterial pathogens, exhibited antimicrobial efficacy against biofilm associated S. aureus and protected against the S. aureus pathogenesis in an animal model of infection. When taken together, our results illustrate that components of the bacterial RNA degradation machinery have utility as antibiotic drug-discovery targets and that RNPA1000 may represent a progenitor of this new class of antibiotics. |
| Databáze: | OpenAIRE |
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