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

PLoS Pathogens

Khalid Sayood¹  Sonja Daily²  Mark S. Smeltzer²  Karen E. Beenken²  Eric P. Skaar³  Michelle L. Reniere³  Jerry W. Simecka⁴  Phung Nguyen⁴  William J. Weiss⁴  Mark Pulse⁴  Christelle M. Roux⁵  Patrick D. Olson⁵  Kelsi L. Anderson⁵  Paul M. Dunman⁵  Tami L. Lewis⁵  John M. Morrison⁵  Lisa J. Kuechenmeister⁵  Oluwatoyin A. Asojo⁵ 

[1] Department of Electrical Engineering, University of Nebraska, Lincoln, Nebraska, United States of America;Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States of America;Department of Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America;Department of Molecular Biology and Immunology, University of North Texas Health Science Center, Fort Worth, Texas, United States of America;Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, United States of America

关键词: Staphylococcus aureus;    Ribonucleases;    Messenger RNA;    Methicillin-resistant Staphylococcus aureus;    Antimicrobials;    Virulence factors;    Antisense RNA;    Vancomycin;   

DOI  :  10.1371/journal.ppat.1001287

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY