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Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis

We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB...

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Autores principales: Gonzalo, Ximena, Bielecka, Magdalena K., Tezera, Liku, Elkington, Paul, Drobniewski, Francis
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598577/
https://www.ncbi.nlm.nih.gov/pubmed/36289932
http://dx.doi.org/10.3390/antibiotics11101274
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author Gonzalo, Ximena
Bielecka, Magdalena K.
Tezera, Liku
Elkington, Paul
Drobniewski, Francis
author_facet Gonzalo, Ximena
Bielecka, Magdalena K.
Tezera, Liku
Elkington, Paul
Drobniewski, Francis
author_sort Gonzalo, Ximena
collection PubMed
description We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB activity (all chosen as conventional drug susceptibility was problematical). PBMCs collected from healthy donors were isolated and infected with M. tuberculosis H37Rv lux (i.e., luciferase). Microspheres were generated with the infected cells; the anti-microbial compounds were added and bacterial luminescence was monitored for at least 21 days. Clavulanate was added to each carbapenem to inhibit beta-lactamases. M. tuberculosis (MTB) killing efficacy was dose dependent. Clofazimine was the most effective drug inhibiting MTB growth at 2 mg/L with good killing activity at both concentrations tested. It was the only drug that killed bacteria at the lowest concentration tested. Carbapenems showed modest initial activity that was lost at around day 10 of incubation and clavulanate did not increase killing activity. Of the carbapenems tested, tebipenem was the most efficient in killing MTB, albeit at a high concentration. Nitazoxanide was effective only at concentrations not achievable with current dosing (although this might partly have been an artefact related to extensive protein binding).
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spelling pubmed-95985772022-10-27 Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis Gonzalo, Ximena Bielecka, Magdalena K. Tezera, Liku Elkington, Paul Drobniewski, Francis Antibiotics (Basel) Article We evaluated a novel physiological 3-D bioelectrospray model of the tuberculosis (TB) granuloma to test the activity of a known anti-TB drug, clofazimine; three carbapenems with potential activity, including one currently used in therapy; and nitazoxanide, an anti-parasitic compound with possible TB activity (all chosen as conventional drug susceptibility was problematical). PBMCs collected from healthy donors were isolated and infected with M. tuberculosis H37Rv lux (i.e., luciferase). Microspheres were generated with the infected cells; the anti-microbial compounds were added and bacterial luminescence was monitored for at least 21 days. Clavulanate was added to each carbapenem to inhibit beta-lactamases. M. tuberculosis (MTB) killing efficacy was dose dependent. Clofazimine was the most effective drug inhibiting MTB growth at 2 mg/L with good killing activity at both concentrations tested. It was the only drug that killed bacteria at the lowest concentration tested. Carbapenems showed modest initial activity that was lost at around day 10 of incubation and clavulanate did not increase killing activity. Of the carbapenems tested, tebipenem was the most efficient in killing MTB, albeit at a high concentration. Nitazoxanide was effective only at concentrations not achievable with current dosing (although this might partly have been an artefact related to extensive protein binding). MDPI 2022-09-20 /pmc/articles/PMC9598577/ /pubmed/36289932 http://dx.doi.org/10.3390/antibiotics11101274 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Gonzalo, Ximena
Bielecka, Magdalena K.
Tezera, Liku
Elkington, Paul
Drobniewski, Francis
Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title_full Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title_fullStr Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title_full_unstemmed Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title_short Anti-Tuberculosis Activity of Three Carbapenems, Clofazimine and Nitazoxanide Using a Novel Ex Vivo Phenotypic Drug Susceptibility Model of Human Tuberculosis
title_sort anti-tuberculosis activity of three carbapenems, clofazimine and nitazoxanide using a novel ex vivo phenotypic drug susceptibility model of human tuberculosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9598577/
https://www.ncbi.nlm.nih.gov/pubmed/36289932
http://dx.doi.org/10.3390/antibiotics11101274
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