Capturing Antibiotic-Resistant Ribosomes
Abstract
This proposal addresses the Topic Area of “Antimicrobial Resistance.” We will develop antibodies that specifically recognize multidrug-resistant m6A-ribosome that can be used as a rapid diagnostic and sensitive biochemical tool. Ribosomes are protein synthesis factories that are essential to all life. The universally conserved nucleotide (A2058) of 23S rRNA in all bacterial ribosomes, when methylated (m6A2058), causes cross-resistance to multiple “highest priority” antibiotics that are ranked on the WHO’s list of essential medicines. The abundance and essentiality of ribosomes make them an attractive target for the detection of resistant pathogens based on the unique m6A2058 signature. Natural or synthetic antibodies specific for m6A-modified RNA are unavailable. If developed, such an unprecedented tool will greatly advance both applied and basic research in at least two areas, namely, clinical diagnostics and basic RNA/ribosome biology, by serving as a capturing tool to isolate homogenous populations of m6A2058-ribosomes for structural and biochemical determination, a critical step to delineate the molecular mechanisms of new ribosome-targeting antibiotics. Conventional methods to detect m6A2058-mediated resistance rely on blood culture-based PCR and antibiotic susceptibility tests that are time-consuming and prone to inaccurate results. An antibody against the m6A2058-ribosome has the potential to detect antibiotic resistance traits directly from blood samples, thereby allowing timely treatment decisions. Anti-RNA antibodies are difficult to obtain compared with those derived from protein or DNA antigens. Successful development of antibodies against the m6A2058-ribosome or m6A-modified RNA will be broadly impactful in RNA biology and therapeutic studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810122
Entities
People
- Mee-Ngan F Yap
Organizations
- Saint Louis University
- United States Army