Pathogenesis and novel treatment against tuberculosis
(2025) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2025:113.- Abstract
- Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains one of the deadliest infectious diseases worldwide. In 2023, it accounted for approximately 1.25 million deaths, including 161,000 among individuals living with HIV, making it the leading cause of death from a single infectious agent. The growing prevalence of multidrug-resistant TB (MDR-TB) further complicates treatment and contributes to the global antimicrobial resistance crisis. Although the WHO-recommended 6-month BPaLM regimen has improved outcomes, novel therapeutic strategies are urgently needed.
This thesis presents three studies aimed at identifying innovative treatment options and exploring under-investigated aspects of TB pathogenesis. The first study... (More) - Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains one of the deadliest infectious diseases worldwide. In 2023, it accounted for approximately 1.25 million deaths, including 161,000 among individuals living with HIV, making it the leading cause of death from a single infectious agent. The growing prevalence of multidrug-resistant TB (MDR-TB) further complicates treatment and contributes to the global antimicrobial resistance crisis. Although the WHO-recommended 6-month BPaLM regimen has improved outcomes, novel therapeutic strategies are urgently needed.
This thesis presents three studies aimed at identifying innovative treatment options and exploring under-investigated aspects of TB pathogenesis. The first study evaluates NZ2114, a plectasin-derived antimicrobial peptide, which demonstrated strong activity against M. bovis BCG (MIC₉₉: 6.1 µM), no cytotoxicity to human cells, and retained efficacy in serum. It also showed activity against Gram-positive pathogens including MRSA and Enterococcus spp.The second study investigates the production of membrane vesicles (MVs) in mycobacteria following exposure to conventional TB antibiotics. While outer membrane vesicles are well-characterized in Gram-negative bacteria, their role in mycobacteria is less understood. Using mass spectrometry and lipidomics, vesicle-associated proteins and lipids were identified. Importantly, mycobacterial MVs induced inflammatory responses, suggesting a role in immune modulation and pathogenesis.The third study explores bacteriophage-derived lysins as alternative therapeutics. Three engineered chimeric lysins showed broad-spectrum activity against M. bovis BCG, M. abscessus, and M. avium, with no toxicity to human macrophages, retained serum activity, and effective intracellular killing.
Together, these findings enhance our understanding of TB pathogenesis and introduce promising therapeutic candidates, antimicrobial peptides and phage-derived enzymes that may help overcome current treatment limitations.
Key words: Tuberculosis, antimicrobial peptides, pathogenesis, vesicles, novel treatment, chimeric lysins
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Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/16028003-a3bf-440b-88a4-bc9812d0c43e
- author
- Davids, Camilla LU
- supervisor
- opponent
-
- Associate professor Brighenti, Susanna, Center for Infectious Medicine (CIM), MedH
- organization
- publishing date
- 2025
- type
- Thesis
- publication status
- published
- subject
- keywords
- Tuberculosis, antimicrobial peptides, pathogenesis, vesicles, novel treatment, chimeric lysins
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- volume
- 2025:113
- pages
- 117 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Dora Jacobsohn, BMC D15, Klinikgatan 32 i Lund
- defense date
- 2025-11-27 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-766-8
- language
- English
- LU publication?
- yes
- id
- 16028003-a3bf-440b-88a4-bc9812d0c43e
- date added to LUP
- 2025-11-04 14:45:35
- date last changed
- 2025-11-06 12:47:50
@phdthesis{16028003-a3bf-440b-88a4-bc9812d0c43e,
abstract = {{Tuberculosis (TB), caused by Mycobacterium tuberculosis, remains one of the deadliest infectious diseases worldwide. In 2023, it accounted for approximately 1.25 million deaths, including 161,000 among individuals living with HIV, making it the leading cause of death from a single infectious agent. The growing prevalence of multidrug-resistant TB (MDR-TB) further complicates treatment and contributes to the global antimicrobial resistance crisis. Although the WHO-recommended 6-month BPaLM regimen has improved outcomes, novel therapeutic strategies are urgently needed.<br/>This thesis presents three studies aimed at identifying innovative treatment options and exploring under-investigated aspects of TB pathogenesis. The first study evaluates NZ2114, a plectasin-derived antimicrobial peptide, which demonstrated strong activity against M. bovis BCG (MIC₉₉: 6.1 µM), no cytotoxicity to human cells, and retained efficacy in serum. It also showed activity against Gram-positive pathogens including MRSA and Enterococcus spp.The second study investigates the production of membrane vesicles (MVs) in mycobacteria following exposure to conventional TB antibiotics. While outer membrane vesicles are well-characterized in Gram-negative bacteria, their role in mycobacteria is less understood. Using mass spectrometry and lipidomics, vesicle-associated proteins and lipids were identified. Importantly, mycobacterial MVs induced inflammatory responses, suggesting a role in immune modulation and pathogenesis.The third study explores bacteriophage-derived lysins as alternative therapeutics. Three engineered chimeric lysins showed broad-spectrum activity against M. bovis BCG, M. abscessus, and M. avium, with no toxicity to human macrophages, retained serum activity, and effective intracellular killing.<br/>Together, these findings enhance our understanding of TB pathogenesis and introduce promising therapeutic candidates, antimicrobial peptides and phage-derived enzymes that may help overcome current treatment limitations.<br/><br/><br/>Key words: Tuberculosis, antimicrobial peptides, pathogenesis, vesicles, novel treatment, chimeric lysins<br/>}},
author = {{Davids, Camilla}},
isbn = {{978-91-8021-766-8}},
issn = {{1652-8220}},
keywords = {{Tuberculosis, antimicrobial peptides, pathogenesis, vesicles, novel treatment, chimeric lysins}},
language = {{eng}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Pathogenesis and novel treatment against tuberculosis}},
url = {{https://lup.lub.lu.se/search/files/232164213/Camilla_Joyce_Davids_-_WEB.pdf}},
volume = {{2025:113}},
year = {{2025}},
}