Sarah Byrd & Dr. Ahmed Awad
Abstract
MRSA has quickly arisen as a hospital superbug, due to causes such as the overuse of antibiotics on livestock, the tendency of patients to stop treatment regimens early when they feel better, and bacterial transformation via plasmids during comorbid infections. In MRSA, this antibiotic resistance is conferred in large part by the ability to produce beta-lactamases inactivating penicillins, as well as the presence of the modified peptidoglycan synthesis protein PBP2a, which penicillins have reduced binding affinity for. Mendoza et al. (2021) proposed PEGA-nucleosides as theoretical drug candidates targeting the class B1 metallo-beta-lactamases NDM-1, IMP-1, and VIM-2; however, their study only considered uridine and adenosine analogues. This multi-term study has built upon Mendoza et al.’s research by performing computational analysis for L- and D- isomers of ten different PEGA-nucleosides in order to see if uridine remained the superior analogue; currently, the pseudouridine analogue performs best. The twenty analogues have been run through SwissADME, admetSAR2.0, and PASS prediction programs to determine various properties and safety profiles; however, as currently administered antibiotics have harmful effects, toxicity was not considered an immediately disqualifying factor. icmMolsoft was used to determine binding energies and protein residue interactions against both PBP2a and the metallo-beta lactamases. Poor candidates, such as the cytidine analogue, have been removed from further study, and the most promising analogues will be synthesized for in vitro and in vivo testing with proteins. Promising results in this step will lead studies of candidates’ effects on both methicillin-resistant model organisms to confirm metallo-beta-lactamase inhibition, and on MRSA to confirm PBP2a inhibition, with Kirby-Bauer diffusion and nitrocefin assays as proposed diagnostics.
Details
Session 2
1:30pm – 2:45pm
Del Norte Hall
Room D: 1530
HSI-SMART
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