Antimycobacterial activity of the plectasin derivative NZ2114
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Published version
Author(s)
Type
Journal Article
Abstract
Introduction: Mycobacteria have a unique hydrophobic membrane with several lipid-enriched layers that are low in permeability, setting them apart from other bacteria. This complex structure, consisting of three distinct layers is crucial for cell growth, virulence, and providing a barrier to antibiotics. Previously, we identified a plectasin variant, NZX, which showed activity against Mycobacterium tuberculosis in several murine tuberculosis (TB) infection studies. In this study, we investigated another plectasin variant, NZ2114, known for its effectiveness against Gram-positive bacteria, as a potential antimycobacterial peptide both in vitro and in vivo.
Methods: The resazurin microtiter assay (REMA) was used to determine MIC; a time-kill assay was performed to evaluate long-term effects; scanning electron microscopy (SEM) was employed to visualize peptide impact; a checkerboard assay assessed drug compatibility; MTT and WST-8 assays were used to estimate peptide toxicity; intracellular killing was evaluated using primary macrophages; peptide stability was assessed in human serum; and a murine tuberculosis (TB) infection model was used to verify the peptide’s efficacy.
Results: NZ2114 effectively killed mycobacteria at a minimal inhibitory concentration (MIC99) of 6.1 µM, was non-toxic to primary human cells, and remained resistant to serum degradation while preserving its antimycobacterial capacity. In a checkerboard assay, NZ2114 demonstrated synergy with the first-line TB drugs isoniazid and ethambutol. The antimicrobial effect was also observed against several clinical isolates of Gram-positive bacteria, including Enterococcus faecalis, Enterococcus faecium, and Methicillin-Resistant Staphylococcus aureus (MRSA). In our murine TB infection model, compared to untreated controls, NZ2114 eliminated M. tuberculosis with a log reduction of 0.72 (81.14%) after three doses.
Discussion: These studies suggest NZ2114 as a potential TB therapy, aiding in the control of this significant infectious disease.
Methods: The resazurin microtiter assay (REMA) was used to determine MIC; a time-kill assay was performed to evaluate long-term effects; scanning electron microscopy (SEM) was employed to visualize peptide impact; a checkerboard assay assessed drug compatibility; MTT and WST-8 assays were used to estimate peptide toxicity; intracellular killing was evaluated using primary macrophages; peptide stability was assessed in human serum; and a murine tuberculosis (TB) infection model was used to verify the peptide’s efficacy.
Results: NZ2114 effectively killed mycobacteria at a minimal inhibitory concentration (MIC99) of 6.1 µM, was non-toxic to primary human cells, and remained resistant to serum degradation while preserving its antimycobacterial capacity. In a checkerboard assay, NZ2114 demonstrated synergy with the first-line TB drugs isoniazid and ethambutol. The antimicrobial effect was also observed against several clinical isolates of Gram-positive bacteria, including Enterococcus faecalis, Enterococcus faecium, and Methicillin-Resistant Staphylococcus aureus (MRSA). In our murine TB infection model, compared to untreated controls, NZ2114 eliminated M. tuberculosis with a log reduction of 0.72 (81.14%) after three doses.
Discussion: These studies suggest NZ2114 as a potential TB therapy, aiding in the control of this significant infectious disease.
Date Issued
2025-06-26
Date Acceptance
2025-06-11
Citation
Frontiers in Microbiology, 2025, 16
ISSN
1664-302X
Publisher
Frontiers Media S.A.
Journal / Book Title
Frontiers in Microbiology
Volume
16
Copyright Statement
© 2025 Davids, Rao-Fransson, Krishnan, Tenland, Mörgelin, Robertson and Godaly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
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Identifier
https://www.ncbi.nlm.nih.gov/pubmed/40641884
Subjects
<italic>Mycobacterium tuberculosis</italic>
INFECTION
Life Sciences & Biomedicine
Microbiology
MYCOBACTERIUM-TUBERCULOSIS
PEPTIDE
peptides
plectasin
Science & Technology
treatment
tuberculosis
Publication Status
Published
Coverage Spatial
Switzerland
Article Number
1613241
Date Publish Online
2025-06-26