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Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs
The emergence of antimicrobial resistance warrants for the development of improved treatment approaches. In this regard, peptide nucleic acids (PNAs) have shown great promise, exhibiting antibiotic properties through the targeting of cellular nucleic acids. We aimed to study the efficacy of PNA as a...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Society for Microbiology
2022
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Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849056/ https://www.ncbi.nlm.nih.gov/pubmed/35171048 http://dx.doi.org/10.1128/spectrum.01262-21 |
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author | Cotta, Karishma Berta Ghosh, Saptarshi Mehra, Sarika |
author_facet | Cotta, Karishma Berta Ghosh, Saptarshi Mehra, Sarika |
author_sort | Cotta, Karishma Berta |
collection | PubMed |
description | The emergence of antimicrobial resistance warrants for the development of improved treatment approaches. In this regard, peptide nucleic acids (PNAs) have shown great promise, exhibiting antibiotic properties through the targeting of cellular nucleic acids. We aimed to study the efficacy of PNA as an anti-tuberculosis agent. Since the efficacy of PNA is limited by its low penetration into the cell, we also investigated combinatorial treatments using permeabilizing drugs to improve PNA efficacy. Various concentrations of anti-inhA PNA, permeabilizing drugs, and their combinations were screened against extracellular and intracellular mycobacteria.0.625 to 5 μM anti-inhA PNA was observed to merely inhibit the growth of extracellular M. smegmatis, while low intracellular bacterial load was reduced by 2 or 2.5 log-fold when treated with 2.5 or 5 μM PNA, respectively. Anti-inhA PNA against M. tuberculosis H37Ra exhibited bactericidal properties at 2.5 and 5 μM and enabled a slight reduction in intracellular M. tuberculosis at concentrations from 2.5 to 20 μM. Of the permeabilizing drugs tested, ethambutol showed the most permeabilizing potential and ultimately potentiated anti-inhA PNA to the greatest extent, reducing its efficacious concentration to 1.25 μM against both M. smegmatis and M. tuberculosis. Furthermore, an enhanced clearance of 1.3 log-fold was observed for ethambutol-anti-inhA PNA combinations against intracellular M. tuberculosis. Thus, permeabilizing drug-PNA combinations indeed exhibit improved efficacies. We therefore propose that anti-inhA PNA could improve therapy even when applied in minute doses as an addition to the current anti-tuberculosis drug regimen. IMPORTANCE Peptide nucleic acids have great potential in therapeutics as anti-gene/anti-sense agents. However, their limited uptake in cells has curtailed their widespread application. Through this study, we explore a PNA-drug combinatorial strategy to improve the efficacy of PNAs and reduce their effective concentrations. This work also focuses on improving tuberculosis treatment, which is hindered by the emergence of antimicrobial-resistant strains of Mycobacterium tuberculosis. It is observed that the antibacterial efficacy of anti-inhA PNA is enhanced when it is combined with permeabilizing drugs, particularly ethambutol. This indicates that the addition of even small concentrations of anti-inhA PNA to the current TB regimen could potentiate their therapeutic efficiency. We hypothesize that this system would also overcome isoniazid resistance, since the resistance mutations lie outside the designed anti-inhA PNA target site. |
format | Online Article Text |
id | pubmed-8849056 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Society for Microbiology |
record_format | MEDLINE/PubMed |
spelling | pubmed-88490562022-02-17 Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs Cotta, Karishma Berta Ghosh, Saptarshi Mehra, Sarika Microbiol Spectr Research Article The emergence of antimicrobial resistance warrants for the development of improved treatment approaches. In this regard, peptide nucleic acids (PNAs) have shown great promise, exhibiting antibiotic properties through the targeting of cellular nucleic acids. We aimed to study the efficacy of PNA as an anti-tuberculosis agent. Since the efficacy of PNA is limited by its low penetration into the cell, we also investigated combinatorial treatments using permeabilizing drugs to improve PNA efficacy. Various concentrations of anti-inhA PNA, permeabilizing drugs, and their combinations were screened against extracellular and intracellular mycobacteria.0.625 to 5 μM anti-inhA PNA was observed to merely inhibit the growth of extracellular M. smegmatis, while low intracellular bacterial load was reduced by 2 or 2.5 log-fold when treated with 2.5 or 5 μM PNA, respectively. Anti-inhA PNA against M. tuberculosis H37Ra exhibited bactericidal properties at 2.5 and 5 μM and enabled a slight reduction in intracellular M. tuberculosis at concentrations from 2.5 to 20 μM. Of the permeabilizing drugs tested, ethambutol showed the most permeabilizing potential and ultimately potentiated anti-inhA PNA to the greatest extent, reducing its efficacious concentration to 1.25 μM against both M. smegmatis and M. tuberculosis. Furthermore, an enhanced clearance of 1.3 log-fold was observed for ethambutol-anti-inhA PNA combinations against intracellular M. tuberculosis. Thus, permeabilizing drug-PNA combinations indeed exhibit improved efficacies. We therefore propose that anti-inhA PNA could improve therapy even when applied in minute doses as an addition to the current anti-tuberculosis drug regimen. IMPORTANCE Peptide nucleic acids have great potential in therapeutics as anti-gene/anti-sense agents. However, their limited uptake in cells has curtailed their widespread application. Through this study, we explore a PNA-drug combinatorial strategy to improve the efficacy of PNAs and reduce their effective concentrations. This work also focuses on improving tuberculosis treatment, which is hindered by the emergence of antimicrobial-resistant strains of Mycobacterium tuberculosis. It is observed that the antibacterial efficacy of anti-inhA PNA is enhanced when it is combined with permeabilizing drugs, particularly ethambutol. This indicates that the addition of even small concentrations of anti-inhA PNA to the current TB regimen could potentiate their therapeutic efficiency. We hypothesize that this system would also overcome isoniazid resistance, since the resistance mutations lie outside the designed anti-inhA PNA target site. American Society for Microbiology 2022-02-16 /pmc/articles/PMC8849056/ /pubmed/35171048 http://dx.doi.org/10.1128/spectrum.01262-21 Text en Copyright © 2022 Cotta et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Cotta, Karishma Berta Ghosh, Saptarshi Mehra, Sarika Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title | Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title_full | Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title_fullStr | Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title_full_unstemmed | Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title_short | Potentiating the Anti-Tuberculosis Efficacy of Peptide Nucleic Acids through Combinations with Permeabilizing Drugs |
title_sort | potentiating the anti-tuberculosis efficacy of peptide nucleic acids through combinations with permeabilizing drugs |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8849056/ https://www.ncbi.nlm.nih.gov/pubmed/35171048 http://dx.doi.org/10.1128/spectrum.01262-21 |
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