title: Small molecule inhibitors of Staphylococcus aureus RnpA alter cellular mRNA turnover, exhibit antimicrobial activity, and attenuate pathogenesis.
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.
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Olson
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Kuechenmeister
authors.forename: Kelsi L
authors.initials: KL
authors.lastname: Anderson
authors.forename: Sonja
authors.initials: S
authors.lastname: Daily
authors.forename: Karen E
authors.initials: KE
authors.lastname: Beenken
authors.forename: Christelle M
authors.initials: CM
authors.lastname: Roux
authors.forename: Michelle L
authors.initials: ML
authors.lastname: Reniere
authors.forename: Tami L
authors.initials: TL
authors.lastname: Lewis
authors.forename: William J
authors.initials: WJ
authors.lastname: Weiss
authors.forename: Mark
authors.initials: M
authors.lastname: Pulse
authors.forename: Phung
authors.initials: P
authors.lastname: Nguyen
authors.forename: Jerry W
authors.initials: JW
authors.lastname: Simecka
authors.forename: John M
authors.initials: JM
authors.lastname: Morrison
authors.forename: Khalid
authors.initials: K
authors.lastname: Sayood
authors.forename: Oluwatoyin A
authors.initials: OA
authors.lastname: Asojo
authors.forename: Mark S
authors.initials: MS
authors.lastname: Smeltzer
authors.forename: Eric P
authors.initials: EP
authors.lastname: Skaar
authors.forename: Paul M
authors.initials: PM
authors.lastname: Dunman
mesh_terms: D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D012323:RNA Processing, Post-Transcriptional / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism*; D043262:Ribonuclease P / Q000037:antagonists & inhibitors* / Q000502:physiology; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity; D014640:Vancomycin / Q000494:pharmacology / Q000627:therapeutic use; D014774:Virulence / Q000187:drug effects / Q000235:genetics
chemical_list: D000890:Anti-Infective Agents; D012333:RNA, Messenger; D054852:Small Molecule Libraries; D014640:Vancomycin; D043262:Ribonuclease P