Rifabutin Is Active against  Mycobacterium abscessus  in Mice

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Abstract

There is no reliable cure for Mycobacterium abscessus lung disease. Rifampin is not used clinically due to poor in vitro potency. In contrast, we have shown that rifabutin, another approved rifamycin used to treat tuberculosis, is potent in vitro against M. abscessus. Here, we report that rifabutin is as active as clarithromycin against M. abscessus K21 in NOD.CB17-Prkdc ^scid/NCrCrl mice. This suggests that rifabutin should be considered a repurposing candidate for patients with M. abscessus disease.

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Most cited references 17

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NTM drug discovery: status, gaps and the way forward.

Mu-Lu Wu, Dinah Aziz, Véronique Dartois … (2018)

Incidence of pulmonary diseases caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing at an alarming rate, surpassing tuberculosis in many countries. Current chemotherapies require long treatment times and the clinical outcomes are often disappointing. There is an urgent medical need to discover and develop new, more-efficacious anti-NTM drugs. In this review, we summarize the current status of NTM drug development, and highlight knowledge gaps and scientific obstacles in NTM drug discovery. We propose strategies to reduce biological uncertainties and to begin to populate a NTM drug pipeline with attractive leads and drug candidates.

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The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

Sakshi Luthra, Anna Rominski, Peter Sander (2018)

The incidence and prevalence of non-tuberculous mycobacterial (NTM) infections have been increasing worldwide and lately led to an emerging public health problem. Among rapidly growing NTM, Mycobacterium abscessus is the most pathogenic and drug resistant opportunistic germ, responsible for disease manifestations ranging from “curable” skin infections to only “manageable” pulmonary disease. Challenges in M. abscessus treatment stem from the bacteria’s high-level innate resistance and comprise long, costly and non-standardized administration of antimicrobial agents, poor treatment outcomes often related to adverse effects and drug toxicities, and high relapse rates. Drug resistance in M. abscessus is conferred by an assortment of mechanisms. Clinically acquired drug resistance is normally conferred by mutations in the target genes. Intrinsic resistance is attributed to low permeability of M. abscessus cell envelope as well as to (multi)drug export systems. However, expression of numerous enzymes by M. abscessus, which can modify either the drug-target or the drug itself, is the key factor for the pathogen’s phenomenal resistance to most classes of antibiotics used for treatment of other moderate to severe infectious diseases, like macrolides, aminoglycosides, rifamycins, β-lactams and tetracyclines. In 2009, when M. abscessus genome sequence became available, several research groups worldwide started studying M. abscessus antibiotic resistance mechanisms. At first, lack of tools for M. abscessus genetic manipulation severely delayed research endeavors. Nevertheless, the last 5 years, significant progress has been made towards the development of conditional expression and homologous recombination systems for M. abscessus. As a result of recent research efforts, an erythromycin ribosome methyltransferase, two aminoglycoside acetyltransferases, an aminoglycoside phosphotransferase, a rifamycin ADP-ribosyltransferase, a β-lactamase and a monooxygenase were identified to frame the complex and multifaceted intrinsic resistome of M. abscessus, which clearly contributes to complications in treatment of this highly resistant pathogen. Better knowledge of the underlying mechanisms of drug resistance in M. abscessus could improve selection of more effective chemotherapeutic regimen and promote development of novel antimicrobials which can overwhelm the existing resistance mechanisms. This article reviews the currently elucidated molecular mechanisms of antibiotic resistance in M. abscessus, with a focus on its drug-target-modifying and drug-modifying enzymes.

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Rifabutin Is Active against Mycobacterium abscessus Complex

Dinah Binte Aziz, Jian Liang Low, Mu-Lu Wu … (2017)

ABSTRACT Lung infections caused by Mycobacterium abscessus are emerging as a global threat to individuals with cystic fibrosis and to other patient groups. Recent evidence for human-to-human transmission worsens the situation. M. abscessus is an intrinsically multidrug-resistant pathogen showing resistance to even standard antituberculosis drugs, such as rifampin. Here, our objective was to identify existing drugs that may be employed for the treatment of M. abscessus lung disease. A collection of more than 2,700 approved drugs was screened at a single-point concentration against an M. abscessus clinical isolate. Hits were confirmed with fresh solids in dose-response experiments. For the most attractive hit, growth inhibition and bactericidal activities against reference strains of the three M. abscessus subspecies and a collection of clinical isolates were determined. Surprisingly, the rifampin derivative rifabutin had MICs of 3 ± 2 μM (3 μg/ml) against the screening strain, the reference strains M. abscessus subsp. abscessus ATCC 19977, M. abscessus subsp. bolletii CCUG 50184-T, and M. abscessus subsp. massiliense CCUG 48898-T, as well as against a collection of clinical isolates. Furthermore, rifabutin was active against clarithromycin-resistant strains. In conclusion, rifabutin, in contrast to rifampin, is active against the Mycobacterium abscessus complex bacteria in vitro and may be considered for treatment of M. abscessus lung disease.

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Journal

Journal ID (nlm-ta): Antimicrob Agents Chemother

Journal ID (iso-abbrev): Antimicrob. Agents Chemother

Journal ID (hwp): aac

Journal ID (pmc): aac

Journal ID (publisher-id): AAC

Title: Antimicrobial Agents and Chemotherapy

Publisher: American Society for Microbiology (1752 N St., N.W., Washington, DC )

ISSN (Print): 0066-4804

ISSN (Electronic): 1098-6596

Publication date (Electronic preprint): 25 November 2019

Publication date (Electronic): 27 January 2020

Publication date Collection: February 2020

Publication date PMC-release: 27 January 2020

Volume: 64

Issue: 2

Electronic Location Identifier: e01943-19

Affiliations

[a ]Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey, USA

[b ]Department of Medical Sciences, Hackensack Meridian School of Medicine at Seton Hall University, Nutley, New Jersey, USA

[c ]Department of Microbiology, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea

[d ]Division of Pulmonary and Critical Care Medicine, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea

[e ]Department of Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, USA

Author notes

Address correspondence to Martin Gengenbacher, martin.gengenbacher@ 123456hmh-cdi.org .

Citation Dick T, Shin SJ, Koh W-J, Dartois V, Gengenbacher M. 2020. Rifabutin is active against Mycobacterium abscessus in mice. Antimicrob Agents Chemother 64:e01943-19. https://doi.org/10.1128/AAC.01943-19.

Author information

Thomas Dick https://orcid.org/0000-0002-9604-9452

Véronique Dartois https://orcid.org/0000-0001-9470-5009

Martin Gengenbacher https://orcid.org/0000-0002-0208-5920

Article

Publisher ID: 01943-19

DOI: 10.1128/AAC.01943-19

PMC ID: 6985736

PubMed ID: 31767722

SO-VID: 5a64727d-e598-454f-9e71-7c058abf7cee

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

History

Date received : 24 September 2019

Date revision requested : 3 November 2019

Date accepted : 19 November 2019

Page count

Figures: 1, Tables: 0, Equations: 0, References: 19, Pages: 3, Words: 2143

Funding

Funded by: HHS | National Institutes of Health (NIH), https://doi.org/10.13039/100000002;

Award ID: R01AI132374

Award ID: U19AI142731

Award Recipient : Thomas Dick

Funded by: HHS | National Institutes of Health (NIH), https://doi.org/10.13039/100000002;

Award ID: R21AI145396

Award Recipient : Martin Gengenbacher

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cover-date February 2020

ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: nontuberculous mycobacteria,ntm,rifamycin,mouse model,animal model

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ScienceOpen disciplines: Infectious disease & Microbiology

Keywords: nontuberculous mycobacteria, ntm, rifamycin, mouse model, animal model

Rifabutin Is Active against Mycobacterium abscessus in Mice

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Drug Repurposing Research Collection

Most cited references 17

NTM drug discovery: status, gaps and the way forward.

The Role of Antibiotic-Target-Modifying and Antibiotic-Modifying Enzymes in Mycobacterium abscessus Drug Resistance

Rifabutin Is Active against Mycobacterium abscessus Complex

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