Evaluation of Novel Atypical Beta-Lactams Against Mycobacterial Ldt Enzymes Toward Combatting Antibiotic Resistance
Abstract
Antimicrobial resistance continues to grow as a global issue. This work aims to combat this concern by investigating L,D-transpeptidase (Ldt) enzymes as potential new drug targets using atypically modified Beta-lactam compounds. Ldts perform an essential function in formation of the peptidoglycan layer of mycobacterial cell walls. These unique Ldt enzymes provide an avenue of drug design by exploiting their essentiality in mycobacterial cell wall biosynthesis and nature specific to mycobacterial infections. There are six evolutionarily distinct classes of mycobacterial Ldts and different mycobacteria species may have all or varying numbers of Ldt classes present. Class 2 Ldts from various mycobacterial species - including that which causes tuberculosis - were the target in this study and were inactivated by both a commercial and synthetic carbapenem, imipenem and compound 10a respectively. Compound 10a is an atypically modified carbapenem, a subclass of beta-lactam, with demonstrated promise as a potential treatment. The two carbapenems of interest were evaluated based on their acylation kinetic profiles generated via stopped-flow tryptophan fluorescence and DynaFit non-linear regression software. Mass spectrometry data supported the nonlinear fits and rate constants produced by DynaFit software. Investigating the acylation kinetics of these compounds will further guide drug design studies toward identifying new Ldt inhibitors.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 16, 2023
- Accession Number
- AD1207067
Entities
People
- Rachel E. Sanborn
Organizations
- United States Naval Academy