Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus
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 antib...
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| Format: | Final Year Project (FYP) |
| Language: | English |
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Nanyang Technological University
2023
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| Online Access: | https://hdl.handle.net/10356/166569 |
| _version_ | 1826128752124362752 |
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| author | Luminary, Audrey Michelle |
| author2 | Kevin Pethe |
| author_facet | Kevin Pethe Luminary, Audrey Michelle |
| author_sort | Luminary, Audrey Michelle |
| collection | NTU |
| description | 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 Building upon unpublished data from our lab, which identified novel combination regimens bactericidal against Mabs, we utilized the combination of cell wall synthesis inhibitors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. |
| first_indexed | 2024-10-01T07:29:42Z |
| format | Final Year Project (FYP) |
| id | ntu-10356/166569 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T07:29:42Z |
| publishDate | 2023 |
| publisher | Nanyang Technological University |
| record_format | dspace |
| spelling | ntu-10356/1665692023-05-08T15:34:03Z Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus Luminary, Audrey Michelle Kevin Pethe School of Biological Sciences kevin.pethe@ntu.edu.sg Science::Biological sciences 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. Bachelor of Science in Biological Sciences 2023-05-05T06:44:17Z 2023-05-05T06:44:17Z 2023 Final Year Project (FYP) Luminary, A. M. (2023). Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus. Final Year Project (FYP), Nanyang Technological University, Singapore. https://hdl.handle.net/10356/166569 https://hdl.handle.net/10356/166569 en application/pdf Nanyang Technological University |
| spellingShingle | Science::Biological sciences Luminary, Audrey Michelle Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title | Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title_full | Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title_fullStr | Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title_full_unstemmed | Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title_short | Investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against Mycobacterium abscessus |
| title_sort | investigating the efficacy and mechanism of action of cell wall synthesis inhibitors against mycobacterium abscessus |
| topic | Science::Biological sciences |
| url | https://hdl.handle.net/10356/166569 |
| work_keys_str_mv | AT luminaryaudreymichelle investigatingtheefficacyandmechanismofactionofcellwallsynthesisinhibitorsagainstmycobacteriumabscessus |