Drug Resistance in Nontuberculous Mycobacteria: Mechanisms and Models

Saxena, Saloni; Spaink, Herman P.; Forn-Cuní, Gabriel

doi:10.3390/biology10020096

Cited by 86 publications

(84 citation statements)

References 209 publications

(144 reference statements)

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“…Another potential explanation could be that NTM bacteria possess a cell envelope up to 20 times less permeable than M. tuberculosis [54]. The lack of activity against M. abscessus was somewhat to be expected since the species shows an intrinsic multidrug resistance [55]. We could therefore conclude that the intracellular activity of the tested compounds does not depend exclusively on their ability to penetrate the mycobacterial wall but also on additional mechanisms that should be further investigated.…”

Section: Ex Vivo Efficacy and Cytotoxicitymentioning

confidence: 93%

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Казакова

Racoviceanu

Petrova

et al. 2021

IJMS

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Twenty lupane type A-ring azepano-triterpenoids were synthesized from betulin and its related derivatives and their antitubercular activity against Mycobacterium tuberculosis, mono-resistant MTB strains, and nontuberculous strains Mycobacterium abscessus and Mycobacterium avium were investigated in the framework of AToMIc (Anti-mycobacterial Target or Mechanism Identification Contract) realized by the Division of Microbiology and Infectious Diseases, NIAID, National Institute of Health. Of all the tested triterpenoids, 17 compounds showed antitubercular activity and 6 compounds were highly active on the H37Rv wild strain (with MIC 0.5 µM for compound 7), out of which 4 derivatives also emerged as highly active compounds on the three mono-resistant MTB strains. Molecular docking corroborated with a machine learning drug-drug similarity algorithm revealed that azepano-triterpenoids have a rifampicin-like antitubercular activity, with compound 7 scoring the highest as a potential M. tuberculosis RNAP potential inhibitor. FIC testing demonstrated an additive effect of compound 7 when combined with rifampin, isoniazid and ethambutol. Most compounds were highly active against M. avium with compound 14 recording the same MIC value as the control rifampicin (0.0625 µM). The antitubercular ex vivo effectiveness of the tested compounds on THP-1 infected macrophages is correlated with their increased cell permeability. The tested triterpenoids also exhibit low cytotoxicity and do not induce antibacterial resistance in MTB strains.

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Section: Ex Vivo Efficacy and Cytotoxicitymentioning

confidence: 93%

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Казакова

Racoviceanu

Petrova

et al. 2021

IJMS

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“…87 Family 1 peroxidase operons are widely distributed in Mycobacteria, including M. tuberculosis and M. leprae, the causative agents of tuberculosis and leprosy, respectively. 88,89 Flp and desulfurase systems are both found in Burkholderia cepacia (pulmonary infections, cystic fibrosis) and Burkholderia pseudomallei (melioidosis) 90 while Nocardia spp. (nocardiosis), Bordetella spp.…”

Section: Family 4 -A-domain Encapsulinsmentioning

confidence: 99%

Large-scale computational discovery and analysis of virus-derived microbial nanocompartments

Andreas

Giessen

2021

Preprint

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Protein compartments represent an important strategy for subcellular spatial control and compartmentalization. Encapsulins are a class of microbial protein compartments defined by the viral HK97-fold of their capsid protein, self-assembly into icosahedral shells, and dedicated cargo loading mechanism for sequestering specific enzymes. Encapsulins are often misannotated and traditional sequence-based searches yield many false positive hits in the form of phage capsids. This has hampered progress in understanding the distribution and functional diversity of encapsulins. Here, we develop an integrated search strategy to carry out a large-scale computational analysis of prokaryotic genomes with the goal of discovering an exhaustive and curated set of all HK97-fold encapsulin-like systems. We report the discovery and analysis of over 6,000 encapsulin-like systems in 31 bacterial and 4 archaeal phyla, including two novel encapsulin families as well as many new operon types that fall within the two already known families. We formulate hypotheses about the biological functions and biomedical relevance of newly identified operons which range from natural product biosynthesis and stress resistance to carbon metabolism and anaerobic hydrogen production. We conduct an evolutionary analysis of encapsulins and related HK97-type virus families and show that they share a common ancestor. We conclude that encapsulins likely evolved from HK97-type bacteriophages. Our study sheds new light on the evolutionary interplay of viruses and cellular organisms, the recruitment of protein folds for novel functions, and the functional diversity of microbial protein organelles.

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“…Additionally, the treatment for NTM infections usually includes a combination of macrolide antibiotics (such as azithromycin and clarithromycin) with aminoglycosides (for fast-growing NTM) or first-line antituberculosis drugs (for slow-growing NTM). However, for some combinations, clinical breakpoints are not well defined, therefore, the effectiveness of treatment can be greatly reduced [5,66]. Generally, many NTM species are naturally resistant to specific drugs, however, improperly adjusted and prolonged treatment regimen leads to the development of acquired resistance in originally drug-sensitive bacterial strains [67].…”

Section: Wgs Perspectives For Diagnostics and Characterization Of Resistance Patterns Of Ntmmentioning

confidence: 99%

“…The pulmonary form of the disease may be manifested by hypersensitivity pneumonitis, nodular bronchiectasis, or fibrovascular disease. Infections caused by NTM have risen rapidly in recent decades, and in many developed countries, the number of cases has exceeded the incidence of pulmonary tuberculosis [5]. In addition, some species of mycobacteria are also associated with increased mortality in domestic, wild animals, or aquatic organisms, thus contributing to high economic damage and negative environmental impact [6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Whole Genome Sequencing in the Management of Non-Tuberculous Mycobacterial Infections

et al. 2021

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Infections caused by non-tuberculous mycobacteria (NTM) have been a public health problem in recent decades and contribute significantly to the clinical and economic burden globally. The diagnosis of infections is difficult and time-consuming and, in addition, the conventional diagnostics tests do not have sufficient discrimination power in species identification due to cross-reactions and not fully specific probes. However, technological advances have been made and the whole genome sequencing (WGS) method has been shown to be an essential part of routine diagnostics in clinical mycobacteriology laboratories. The use of this technology has contributed to the characterization of new species of mycobacteria, as well as the identification of gene mutations encoding resistance and virulence factors. Sequencing data also allowed to track global outbreaks of nosocomial NTM infections caused by M. abscessus complex and M. chimaera. To highlight the utility of WGS, we summarize recent scientific studies on WGS as a tool suitable for the management of NTM-induced infections in clinical practice.

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Drug Resistance in Nontuberculous Mycobacteria: Mechanisms and Models

Cited by 86 publications

References 209 publications

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

Large-scale computational discovery and analysis of virus-derived microbial nanocompartments

Whole Genome Sequencing in the Management of Non-Tuberculous Mycobacterial Infections

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