Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria

Soni, Isha; Groote, Mary Ann De; Dasgupta, Arunava; Chopra, Sidharth

doi:10.1099/jmm.0.000198

Cited by 46 publications

(24 citation statements)

References 36 publications

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“…Despite an urgent medical need to discover new antimycobacterials or repurpose existing drugs, there is a distinct lack of activity and progress in drug discovery for treating NTM infections (1, 11, 23–25). Here, we asked whether the repertoire of existing drugs and antibiotics may contain overlooked medicines showing anti-M.…”

Section: Introductionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

129

167

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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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Section: Introductionmentioning

confidence: 99%

Rifabutin Is Active against Mycobacterium abscessus Complex

Aziz

Low

et al. 2017

Antimicrob Agents Chemother

129

167

View full text Add to dashboard Cite

show abstract

“…tuberculosis , they constitute a major cause of opportunistic infections in HIV patients 4 . Alarmingly, the number of reported cases has been increasing worldwide 2 , 5 . NTM also colonize man-made environments and cause healthcare-associated infections, which are a major public health concern 2 – 4 .…”

Section: Introductionmentioning

confidence: 99%

HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness

Lefebvre

Boulon

Ducoux

et al. 2018

Sci Rep

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Mycolic acids (MAs) have a strategic location within the mycobacterial envelope, deeply influencing its architecture and permeability, and play a determinant role in the pathogenicity of mycobacteria. The fatty acid synthase type II (FAS-II) multienzyme system is involved in their biosynthesis. A combination of pull-downs and proteomics analyses led to the discovery of a mycobacterial protein, HadD, displaying highly specific interactions with the dehydratase HadAB of FAS-II. In vitro activity assays and homology modeling showed that HadD is, like HadAB, a hot dog folded (R)-specific hydratase/dehydratase. A hadD knockout mutant of Mycobacterium smegmatis produced only the medium-size alpha’-MAs. Data strongly suggest that HadD is involved in building the third meromycolic segment during the late FAS-II elongation cycles, leading to the synthesis of the full-size alpha- and epoxy-MAs. The change in the envelope composition induced by hadD inactivation strongly altered the bacterial fitness and capacities to aggregate, assemble into colonies or biofilms and spread by sliding motility, and conferred a hypersensitivity to the firstline antimycobacterial drug rifampicin. This showed that the cell surface properties and the envelope integrity were greatly affected. With the alarmingly increasing case number of nontuberculous mycobacterial diseases, HadD appears as an attractive target for drug development.

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“…Relatively little research has been done utilizing animal models to develop new therapies for NTM generally ( Soni et al, 2016 ) and M. kansasii infection specifically. Research into the efficacy of compounds has largely been limited to drugs currently in use to treat tuberculosis or licensed drugs such as quinolones and macrolides.…”

Section: Animal Studiesmentioning

confidence: 99%

Therapy for Mycobacterium kansasii Infection: Beyond 2018

2018

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The current standard of care therapy for pulmonary Mycobacterium kansasii infection is isoniazid (300 mg/day), rifampin (600 mg/day), and ethambutol (15 mg/kg/day) for 12 months after achieving sputum culture negativity. Rifampin is the key drug in this regimen. The contribution of isoniazid is unclear since its in vitro MICs against M. kansasii are near the peak achievable serum levels and more than 100-fold greater than the MICs for Mycobacterium tuberculosis. Ethambutol likely decreases the emergence of rifampin resistant organisms. There are several new drug classes (e.g., quinolones, macrolides, nitroimidazoles, diarylquinolines, and clofazimine) that exhibit antimycobacterial activities against M. tuberculosis but have not yet been adequately studied against M. kansasii infections. The evaluation of in vitro activities of these agents as well as their study in new regimens in comparison to the standard of care regimen in mouse infection models should be undertaken. This knowledge will inform development of human clinical trials of new regimens in comparison to the current standard of care regimen. It is likely that shorter and more effective therapy is achievable with currently available drugs.

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Challenges facing the drug discovery pipeline for non-tuberculous mycobacteria

Cited by 46 publications

References 36 publications

Rifabutin Is Active against Mycobacterium abscessus Complex

Rifabutin Is Active against Mycobacterium abscessus Complex

HadD, a novel fatty acid synthase type II protein, is essential for alpha- and epoxy-mycolic acid biosynthesis and mycobacterial fitness

Therapy for Mycobacterium kansasii Infection: Beyond 2018

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