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ORIGINAL RESEARCH article

Front. Trop. Dis
Sec. Major Tropical Diseases
Volume 5 - 2024 | doi: 10.3389/fitd.2024.1413211
This article is part of the Research Topic Newer Initiatives in Detection, Drug Discovery and Therapeutic Management of Drug-Resistant Tuberculosis View all 3 articles

Apramycin kills replicating and non-replicating Mycobacterium tuberculosis

Provisionally accepted
Parvinder Kaur Parvinder Kaur 1*Ramya VK Ramya VK 1Naveenkumar CN Naveenkumar CN 1Bharathkumar K Bharathkumar K 1Mayas Singh Mayas Singh 1Sven N. Hobbie Sven N. Hobbie 2RK SHANDIL RK SHANDIL 1Shridhar Narayanan Shridhar Narayanan 1
  • 1 Foundation for Neglected Disease Research (FNDR), Bangalore, India
  • 2 Personalized Health Basel, University of Basel, Basel, Switzerland

The final, formatted version of the article will be published soon.

    Mycobacterium 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. Here, 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. In 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). The results indicate the potential of apramycin-based combinations for the treatment of human tuberculosis. Keywords: Mycobacterium tuberculosis (Mtb), Multidrug resistance (MDR), Planktonic, Biofilm (BF)

    Keywords: Mycobacterium tuberculosis (MTB), Multidrug resistance (MDR), planktonic, Biofilm (BF) Apramycin, aminoglycoside, Mycobacterium tuberculosis, Drug Resistance, pre-clinical

    Received: 24 Apr 2024; Accepted: 08 Jul 2024.

    Copyright: © 2024 Kaur, VK, CN, K, Singh, Hobbie, SHANDIL and Narayanan. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Parvinder Kaur, Foundation for Neglected Disease Research (FNDR), Bangalore, India

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