We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Epitranscriptional m<sup>6</sup>A modification of rRNA negatively impacts translation and host colonization in Staphylococcus aureus.
- Authors
Shields, Kathryn E.; Ranava, David; Tan, Yongjun; Zhang, Dapeng; Yap, Mee-Ngan F.
- Abstract
Macrolides, lincosamides, and streptogramin B (MLS) are structurally distinct molecules that are among the safest antibiotics for prophylactic use and for the treatment of bacterial infections. The family of erythromycin resistance methyltransferases (Erm) invariantly install either one or two methyl groups onto the N6,6-adenosine of 2058 nucleotide (m6A2058) of the bacterial 23S rRNA, leading to bacterial cross-resistance to all MLS antibiotics. Despite extensive structural studies on the mechanism of Erm-mediated MLS resistance, how the m6A epitranscriptomic mark affects ribosome function and bacterial physiology is not well understood. Here, we show that Staphylococcus aureus cells harboring m6A2058 ribosomes are outcompeted by cells carrying unmodified ribosomes during infections and are severely impaired in colonization in the absence of an unmodified counterpart. The competitive advantage of m6A2058 ribosomes is manifested only upon antibiotic challenge. Using ribosome profiling (Ribo-Seq) and a dual-fluorescence reporter to measure ribosome occupancy and translational fidelity, we found that specific genes involved in host interactions, metabolism, and information processing are disproportionally deregulated in mRNA translation. This dysregulation is linked to a substantial reduction in translational capacity and fidelity in m6A2058 ribosomes. These findings point to a general "inefficient translation" mechanism of trade-offs associated with multidrug-resistant ribosomes. Author summary: The Erm rRNA methyltransferases are widespread among nosocomial and commensal Gram-negative and Gram-positive bacteria. Upon exposure to sublethal doses of macrolide antibiotics, the expression of erm genes is upregulated, and Erm enzymes exquisitely methylate the universally conserved A2058 nucleotide of 23S rRNA in the bacterial ribosomes (m6A2058 ribosomes). The m6A mark prevents binding of all three clinically important classes of antibiotics (macrolides, lincosamides and streptogramin B (MLS)). While the mechanism of MLS resistance has been studied extensively, how the methylation affects protein synthesis and bacterial fitness is less well understood. We show that human pathogenic Staphylococcus aureus cells bearing m6A2058 ribosomes are defective in colonizing animals and have inferior competitive fitness to cells carrying unmodified ribosomes. Global and targeted translation analyses revealed that m6A2058 ribosomes exhibit decreased overall translational efficiency. Our data add to a growing list of examples linking fitness cost to the acquisition of resistance genes.
- Subjects
GENETIC translation; COLONIZATION (Ecology); BACTERIAL colonies; STAPHYLOCOCCUS aureus; MACROLIDE antibiotics; RIBOSOMAL RNA
- Publication
PLoS Pathogens, 2024, Vol 20, Issue 1, p1
- ISSN
1553-7366
- Publication type
Article
- DOI
10.1371/journal.ppat.1011968