PhD Oral Exam - Dalia Ali, Chemistry and Biochemistry

When studying for a doctoral degree (PhD), candidates submit a thesis that provides a critical review of the current state of knowledge of the thesis subject as well as the student’s own contributions to the subject. The distinguishing criterion of doctoral graduate research is a significant and original contribution to knowledge.

Once accepted, the candidate presents the thesis orally. This oral exam is open to the public.

Abstract

Bacterial infections pose a global health threat, not only because they lead to serious complications, but also due to the alarming rise in antibiotic resistance, rendering many treatments ineffective. This necessitates the development of new strategies for antibiotic delivery to combat these infections, especially through inhalation and topical applications, which could provide a highly localized treatment with minimal systemic toxicity.

Antimicrobial peptides, such as GL13K, have emerged as potent candidates due to their high binding selectivity towards bacterial membranes, while typically not affecting healthy mammalian cells at therapeutic concentrations. However, the systemic delivery of these peptides can be challenging since they suffer from enzymatic hydrolysis and rapid elimination. Similarly, Amikacin (AMK), a semi-synthetic aminoglycoside antibiotic active against both gram-positive and gram-negative bacteria, presents its own delivery challenges. The high hydrophilicity of this antibiotic, along with its high toxicity (nephrotoxicity and ototoxicity), limit its clinical use.

In this thesis, GL13K or AMK were loaded into native phytoglycogen (PG), carboxymethylated phytoglycogen (CMPG), and/or polyphosphate (GS) through electrostatic interactions to investigate their potentials in the delivery of these antimicrobials. Loading capacity and release profile under physiological conditions were assessed for GL13K or AMK. Physicochemical characterization of the loaded nanoparticles, including particle size, surface charge, and liquid stability studies, were performed. Moreover, the antimicrobial activity against different bacterial strains including a hardened lung pathogen, Pseudomonas aeruginosa, as well as toxicity on lung cells were evaluated. We show that the drug loading capacity and release kinetics are dependant on the physical properties, structural characteristics, and binding affinities of both the carrier and the drug, which dictate their antimicrobial efficacy. We also demonstrate that the release can be further controlled using a stimuli-degradable polymer.

This thesis explores the use of electrostatic association as a simple, green approach to developing antimicrobial nanoparticle delivery systems. We demonstrate the tunability of these systems toward specific target bacteria and environmental release conditions through the rational selection of the drug and polymer combinations. These findings establish a versatile platform that can be adapted for a wide range of therapeutic and clinical applications.