Apramycin kills replicating and non-replicating Mycobacterium tuberculosis
IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past,...
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ftdoajarticles:oai:doaj.org/article:6548c854173141199271968ab94f6105 2024-09-09T19:26:27+00:00 Apramycin kills replicating and non-replicating Mycobacterium tuberculosis Parvinder Kaur Ramya V. K. Naveenkumar C. N. Bharathkumar K. Mayas Singh Sven N. Hobbie Radha Krishan Shandil Shridhar Narayanan 2024-08-01T00:00:00Z https://doi.org/10.3389/fitd.2024.1413211 https://doaj.org/article/6548c854173141199271968ab94f6105 EN eng Frontiers Media S.A. https://www.frontiersin.org/articles/10.3389/fitd.2024.1413211/full https://doaj.org/toc/2673-7515 2673-7515 doi:10.3389/fitd.2024.1413211 https://doaj.org/article/6548c854173141199271968ab94f6105 Frontiers in Tropical Diseases, Vol 5 (2024) Mycobacterium tuberculosis (Mtb) multidrug resistance (MDR) planktonic biofilm (BF) apramycin replicating Arctic medicine. Tropical medicine RC955-962 article 2024 ftdoajarticles https://doi.org/10.3389/fitd.2024.1413211 2024-08-26T15:21:18Z IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.MethodsHere, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.ResultsIn standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).DiscussionThe results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis. Article in Journal/Newspaper Arctic Directory of Open Access Journals: DOAJ Articles Arctic Frontiers in Tropical Diseases 5 |
institution |
Open Polar |
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Directory of Open Access Journals: DOAJ Articles |
op_collection_id |
ftdoajarticles |
language |
English |
topic |
Mycobacterium tuberculosis (Mtb) multidrug resistance (MDR) planktonic biofilm (BF) apramycin replicating Arctic medicine. Tropical medicine RC955-962 |
spellingShingle |
Mycobacterium tuberculosis (Mtb) multidrug resistance (MDR) planktonic biofilm (BF) apramycin replicating Arctic medicine. Tropical medicine RC955-962 Parvinder Kaur Ramya V. K. Naveenkumar C. N. Bharathkumar K. Mayas Singh Sven N. Hobbie Radha Krishan Shandil Shridhar Narayanan Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
topic_facet |
Mycobacterium tuberculosis (Mtb) multidrug resistance (MDR) planktonic biofilm (BF) apramycin replicating Arctic medicine. Tropical medicine RC955-962 |
description |
IntroductionMycobacterium tuberculosis (Mtb) has the capability to dodge the immune system by escaping into alternate physiological forms by forming drug tolerant populations under the immune pressure in the host. New drugs are urgently needed to treat these non-replicating persisters. In the past, aminoglycoside antibiotics have played a pivotal role in TB chemotherapy.MethodsHere, we explored the therapeutic potential of a monosubstituted deoxystreptamine aminoglycoside, apramycin (APR) which is different in its chemical structure from the other clinically relevant aminoglycoside antibiotics that are all disubstituted, e.g., amikacin (AMI). We determined the APR MIC as 0.25-1 µg/ml for sensitive and multidrug-resistant Mtb (MDRTB), including amikacin (AMI) resistant strains.ResultsIn standard time-kill kinetic assays, the bactericidal activity of APR was similar to that of AMI demonstrating dose-dependent killing of planktonic Mtb. However, in biofilm and macrophage intracellular killing assays, APR appeared significantly more potent than AMI. Further, APR monotherapy was efficacious in a mouse chronic TB lung infection model (~0.92 log10 CFU/lung reduction). APR combination therapy with the current 1st line standard of care (SoC) antibiotic combination of isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z) was found to be additive (HREZ=1.88 vs. HREZ-APR=2.78 log10CFU/lung reduction).DiscussionThe results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis. |
format |
Article in Journal/Newspaper |
author |
Parvinder Kaur Ramya V. K. Naveenkumar C. N. Bharathkumar K. Mayas Singh Sven N. Hobbie Radha Krishan Shandil Shridhar Narayanan |
author_facet |
Parvinder Kaur Ramya V. K. Naveenkumar C. N. Bharathkumar K. Mayas Singh Sven N. Hobbie Radha Krishan Shandil Shridhar Narayanan |
author_sort |
Parvinder Kaur |
title |
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
title_short |
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
title_full |
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
title_fullStr |
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
title_full_unstemmed |
Apramycin kills replicating and non-replicating Mycobacterium tuberculosis |
title_sort |
apramycin kills replicating and non-replicating mycobacterium tuberculosis |
publisher |
Frontiers Media S.A. |
publishDate |
2024 |
url |
https://doi.org/10.3389/fitd.2024.1413211 https://doaj.org/article/6548c854173141199271968ab94f6105 |
geographic |
Arctic |
geographic_facet |
Arctic |
genre |
Arctic |
genre_facet |
Arctic |
op_source |
Frontiers in Tropical Diseases, Vol 5 (2024) |
op_relation |
https://www.frontiersin.org/articles/10.3389/fitd.2024.1413211/full https://doaj.org/toc/2673-7515 2673-7515 doi:10.3389/fitd.2024.1413211 https://doaj.org/article/6548c854173141199271968ab94f6105 |
op_doi |
https://doi.org/10.3389/fitd.2024.1413211 |
container_title |
Frontiers in Tropical Diseases |
container_volume |
5 |
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1809896055135797248 |