Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis.
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...
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2011
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oai:doaj.org-article:78e41f54ca3e43d185ba27c4529fcda92021-11-18T06:03:36ZSmall molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis.1553-73661553-737410.1371/journal.ppat.1001287https://doaj.org/article/78e41f54ca3e43d185ba27c4529fcda92011-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/21347352/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374Methicillin-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.Patrick D OlsonLisa J KuechenmeisterKelsi L AndersonSonja DailyKaren E BeenkenChristelle M RouxMichelle L ReniereTami L LewisWilliam J WeissMark PulsePhung NguyenJerry W SimeckaJohn M MorrisonKhalid SayoodOluwatoyin A AsojoMark S SmeltzerEric P SkaarPaul M DunmanPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 7, Iss 2, p e1001287 (2011) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 |
| spellingShingle |
Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Patrick D Olson Lisa J Kuechenmeister 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 Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| description |
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. |
| format |
article |
| author |
Patrick D Olson Lisa J Kuechenmeister 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 |
| author_facet |
Patrick D Olson Lisa J Kuechenmeister 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 |
| author_sort |
Patrick D Olson |
| title |
Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| title_short |
Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| title_full |
Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| title_fullStr |
Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| title_full_unstemmed |
Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| title_sort |
small molecule inhibitors of staphylococcus aureus rnpa alter cellular mrna turnover, exhibit antimicrobial activity, and attenuate pathogenesis. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2011 |
| url |
https://doaj.org/article/78e41f54ca3e43d185ba27c4529fcda9 |
| work_keys_str_mv |
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