Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus

• Main Author: Luminary, Audrey Michelle
• Other Authors: Kevin Pethe
• Format: Final Year Project
• Language: English
• Published: Nanyang Technological University 2023
• Subjects: Science::Biological sciences
• Online Access: https://hdl.handle.net/10356/166569
• Institution: Nanyang Technological University

Mycobacterium abscessus (Mabs) is an emerging opportunistic pathogen associated with severe pulmonary infections. As the worldwide prevalence of these infections remains on the rise, current treatment regimens have been proven largely ineffective, aggravated by intrinsic resistance to numerous antibiotics. We sought to bridge the gap in the drug discovery pipeline by evaluating novel drug combinations with synergistic bactericidal activity. Building upon unpublished data from our lab, which identified novel combination regimens bactericidal against Mabs, we utilized the combination of cell wall synthesis inhibitors belonging to the glycopeptides and β-lactams group of antibiotics targeting peptidoglycan synthesis. Our in-vitro studies have shown that the combinations of Glyco-1 and Glyco-2 with Blact-1 exhibited synergistic bactericidal effect, resulting in a remarkable reduction of up to 3-log10 and 5-log10 in bacterial viability for replicating and non-replicating Mabs respectively. Moreover, our findings revealed that even solo glycopeptides and β-lactams treatment at bactericidal concentrations exhibited slower killing, of up to 2-log10 reduction against nutrient-starved Mabs, which is not evident in replicating Mabs. Furthermore, our preliminary investigations using peptidoglycan analog probes revealed that the glycopeptides most likely inhibit L,D-transpeptidases (LDT) under nutrient-starved conditions. These results provide a basis for a new therapeutic strategy in eradicating Mabs infections.