Anti-tuberculosis activity of three carbapenems, clofazimine and nitazoxanide using a novel ex vivo phenotypic drug susceptibility model of human tuberculosis
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 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).
anti-microbial drug resistance, drug susceptibility testing, three-dimensional bioelectrospray, tuberculosis
Gonzalo, Ximena
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Bielecka, Magdalena K.
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Tezera, Liku Bekele
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Elkington, Paul
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Drobniewski, Francis A.
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October 2022
Gonzalo, Ximena
a0b70b5f-a2b6-4aa4-8835-036d60a65f7d
Bielecka, Magdalena K.
90391ea3-aa1f-4104-a893-568c138718a2
Tezera, Liku Bekele
c5598dbf-23a8-4934-96a4-7c783bf9e776
Elkington, Paul
60828c7c-3d32-47c9-9fcc-6c4c54c35a15
Drobniewski, Francis A.
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Gonzalo, Ximena, Bielecka, Magdalena K., Tezera, Liku Bekele, Elkington, Paul and Drobniewski, Francis A.
(2022)
Anti-tuberculosis activity of three carbapenems, clofazimine and nitazoxanide using a novel ex vivo phenotypic drug susceptibility model of human tuberculosis.
Antibiotics, 11 (10), [1274].
(doi:10.3390/antibiotics11101274).
Abstract
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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antibiotics-11-01274 (1)
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Antibiotics_author_accepted_190922
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Accepted/In Press date: 19 September 2022
Published date: October 2022
Additional Information:
Funding Information:
F.D. was partly supported by the Imperial Biomedical Research Center and EU Grant CARE (Project Grant 825673). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. P.E., M.K.B., L.T. and F.D. were supported by MRC grant MR/N006631/1—Investigating multi-drug resistant tuberculosis in the 3-dimensional bioelectrospray cell culture model.
Publisher Copyright:
© 2022 by the authors.
Keywords:
anti-microbial drug resistance, drug susceptibility testing, three-dimensional bioelectrospray, tuberculosis
Identifiers
Local EPrints ID: 470557
URI: http://eprints.soton.ac.uk/id/eprint/470557
ISSN: 2079-6382
PURE UUID: 90fe0438-7430-4783-a8c0-4dbd2b46ad26
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Date deposited: 13 Oct 2022 16:30
Last modified: 17 Mar 2024 03:30
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Author:
Ximena Gonzalo
Author:
Magdalena K. Bielecka
Author:
Francis A. Drobniewski
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