ORIGINAL RESEARCH article
Front. Microbiol.
Sec. Antimicrobials, Resistance and Chemotherapy
Volume 16 - 2025 | doi: 10.3389/fmicb.2025.1604400
This article is part of the Research TopicAdvancements in Combatting Nontuberculous Mycobacterial Infections: Mechanisms and TreatmentsView all articles
Evaluation of the cytotoxicity and antibacterial activity of a synthetic tunicamycin derivative against Mycobacterium avium complex
Provisionally accepted
- 1National Animal Disease Center, Agricultural Research Service (USDA), Ames, Iowa, United States
- 2CONICET Institute of Agrobiotechnology and Molecular Biology (IABIMO), Castelar, Argentina
- 3Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, Tennessee, United States
- 4National Center for Agricultural Utilization Research, Agricultural Research Service (USDA), Peoria, Illinois, United States
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Two synthetic derivatives of the tunicamycin antibiotic, TunR1 and TunR2, were previously developed that significantly reduced toxicity in eukaryotes but remained potent against Gram positive prokaryotes. TunR2 has been demonstrated to be non-toxic and effective in a zebrafish model of mycobacterial infection. In this study, we evaluated the cytotoxicity in bovine cells and the antibacterial effect of natural Tun as well as two synthetic derivatives of Tun, designated TunR1 and TunR2, on Mycobacterium avium complex. The average minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) for TunR2 ranged from 16 to 32 µg/mL when tested on seven Mycobacterium avium subspecies paratuberculosis (Map) strains.MICs were higher for the closely related Mycobacterium avium subspecies hominissuis (>32 µg/mL), and lower for M. marinum (0.025 µg/mL) and M. smegmatis (3.2 µg/mL). Effects on the Map cell wall could be detected by electron microscopy at TunR2 concentrations above 128 µg/mL. The toxicity of TunR2 in eukaryotes was evaluated in vitro by hemolysis of bovine red blood cells (RBCs) and by MTT viability assay on a bovine epithelial cell line, cultured bovine peripheral blood mononuclear cells (PBMCs), and bovine monocyte-derived macrophages (bMDMs). The concentrations of the drug that produce 50% of inhibition (IC50) in each of these three cell types was lower than the MIC for Map. Hemolytic activity was demonstrated in 91% of RBCs when exposed to 31 µg/mL of TunR2. Also, low-dose TunR2 treatment of infected macrophages did not significantly decrease Map survival after 48h of infection. These results suggest that TunR2 is not a good candidate to treat Map infections.
Keywords: Tunicamycin, Mycobacterium avium complex (MAC), Mycobacterium paratuberculosis (MAP), Cytotocixicity, Minimal Inhibition Concentration (MIC)
Received: 01 Apr 2025; Accepted: 29 Apr 2025.
Copyright: © 2025 Colombatti Olivieri, Price, Jackson and Bannantine. 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) or licensor 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.
* Correspondence: María Alejandra Colombatti Olivieri, National Animal Disease Center, Agricultural Research Service (USDA), Ames, 50010, Iowa, United States
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