Mycobacterium tuberculosis β-lactamase variant reduces sensitivity to ampicillin/avibactam in a zebrafish-Mycobacterium marinum model of tuberculosis.
Autor: | van Alen I; Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands., Aguirre García MA; Institute of Biology Leiden, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands., Maaskant JJ; Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VUmc, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands., Kuijl CP; Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VUmc, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands., Bitter W; Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VUmc, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.; Section of Molecular Microbiology, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands., Meijer AH; Institute of Biology Leiden, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands., Ubbink M; Leiden Institute of Chemistry, Leiden University, Einsteinweg 55, 2333CC, Leiden, The Netherlands. m.ubbink@chem.leidenuniv.nl. |
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Jazyk: | angličtina |
Zdroj: | Scientific reports [Sci Rep] 2023 Sep 16; Vol. 13 (1), pp. 15406. Date of Electronic Publication: 2023 Sep 16. |
DOI: | 10.1038/s41598-023-42152-8 |
Abstrakt: | The β-lactamase of Mycobacterium tuberculosis, BlaC, hydrolyzes β-lactam antibiotics, hindering the use of these antibiotics for the treatment of tuberculosis. Inhibitors, such as avibactam, can reversibly inhibit the enzyme, allowing for the development of combination therapies using both antibiotic and inhibitor. However, laboratory evolution studies using Escherichia coli resulted in the discovery of single amino acid variants of BlaC that reduce the sensitivity for inhibitors or show higher catalytic efficiency against antibiotics. Here, we tested these BlaC variants under more physiological conditions using the M. marinum infection model of zebrafish, which recapitulates hallmark features of tuberculosis, including the intracellular persistence of mycobacteria in macrophages and the induction of granuloma formation. To this end, the M. tuberculosis blaC gene was integrated into the chromosome of a blaC frameshift mutant of M. marinum. Subsequently, the resulting strains were used to infect zebrafish embryos in order to test the combinatorial effect of ampicillin and avibactam. The results show that embryos infected with an M. marinum strain producing BlaC show lower infection levels after treatment than untreated embryos. Additionally, BlaC K234R showed higher infection levels after treatment than those infected with bacteria producing the wild-type enzyme, demonstrating that the zebrafish host is less sensitive to the combinatorial therapy of β-lactam antibiotic and inhibitor. These findings are of interest for future development of combination therapies to treat tuberculosis. (© 2023. Springer Nature Limited.) |
Databáze: | MEDLINE |
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