Sarah Byrd and Dr. Ahmed Awad
Abstract
One of the largest threats to healthcare today is the rise of multidrug-resistant pathogens, such as MRSA. 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 and transduction via plasmids during comorbid infections have selected for strains that can resist nearly all current antibiotics. In MRSA, this resistance is conferred by the ability to produce beta-lactamases which inactivate penicillins, as well as the presence of the modified peptidoglycan synthesis protein PBP2a, which penicillins have a 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 in part seeks to build upon Mendoza et al.’s research by performing computational analysis for two isomers each of ten different PEGA-nucleosides, in order to see if uridine remains the superior analogue. Currently, the twenty analogues have been designed, and ran through SwissADME, ProToxII, and PASS prediction programs to determine various properties and safety profiles. ICM Molsoft will be used to calculate binding energies and amino acid residues the analogues bind with. Additional docking studies will be conducted to see if the analogues can disrupt PBP2a function, serving as a dual-action drug that can negate both of MRSA’s resistance mechanisms. Poor candidates will be removed from further study, with the most promising analogues 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.
Presentation
Session 2 – 3:00p.m. – 4:15p.m.
Room D – Sierra 2422
