Degree
Doctor of Philosophy (PhD)
Department
Chemistry
Document Type
Dissertation
Abstract
The carbapenem-resistant Pseudomonas aeruginosa and Acinetobacter baumannii strains have been listed by the World Health Organization (WHO) as top-priority organisms for the development of new antibiotics. P. aeruginosa and A. baumannii are Gram-negative bacteria characterized by an impermeable outer membrane, which has presented a formidable barrier to the development of antibiotics. Our research focuses on understanding and validating bacterial iron homeostasis as a target for antibiotic development. Our work has shown that in P. aeruginosa, the complex formed by bacterioferritin (BfrB) and its associated ferredoxin (Bfd) is required for iron homeostasis. The structure of the BfrB:Bfd complex from P. aeruginosa supported a structure-guided process of small molecule design and optimization that led to 4-aminoisoindoline-1,3-dione analogues. These small molecules have been shown to inhibit the BfrB:Bfd interaction and kill biofilm-embedded bacteria. Genomic data suggests that the Bfr:Bfd interaction is conserved in Acinetobacter baumannii. Consequently, the small molecule inhibitors were tested against the highly virulent A. baumannii AB5075 and ATCC17978 and found to be active.
This dissertation will discuss computational and analytical methods implemented to gain insight into the structure-activity relationships enabling these molecules to engage their Bfr target with high affinity and penetrate the Gram-negative envelope efficiently. To these ends, we implemented a computational investigation to determine how structural modifications to the small molecules impact their residency time on Bfr, and developed a fluorescence-based assay to determine how structure enables intracellular accumulation in P. aeruginosa and A. baumannii.
Conducting these measurements with a series of 4-(benzylamino)isoindoline-1,3-dione analogues demonstrated that the intracellular accumulation increases with (i) the presence of halogen at position 5 of the benzylamino ring (ii) increased bulkiness of the halogen, and (iii) aromaticity of the analogues. Importantly, increased intracellular accumulation is proportional to antibacterial activity in both organisms. Together, these measurements are contributing to ongoing efforts to improve inhibitors at hand into drug-lead molecules.
Date
8-23-2024
Recommended Citation
Alli, Suliat A., "STRUCTURE-ACTIVITY RELATIONSHIPS OF SMALL MOLECULES DESIGNED TO INHIBIT THE BACTERIOFERRITIN-FERREDOXIN COMPLEX AND PERTURB IRON METABOLISM IN PATHOGENIC BACTERIA" (2024). LSU Doctoral Dissertations. 6588.
https://repository.lsu.edu/gradschool_dissertations/6588
Committee Chair
Rivera, Mario