Comparing the Metabolic Capabilities of Bacteria in the Mycobacterium tuberculosis Complex

Fieweger, Rachael A; Wilburn, Kaley M; VanderVen, Brian C.

doi:10.3390/microorganisms7060177

Cited by 20 publications

(26 citation statements)

References 189 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Recent evidence also demonstrated the importance of this metabolic pathway in virulence and pathogenesis of mycobacteria 23 – 27 . Cholesterol was found to be utilised by MTB for not only the energy production and gluconeogenesis, but also for the biosynthesis of lipid virulent factors, such as phthiocerol-dimycocerosate (PDIM) and sulfolipids (SLs) 28 .…”

Section: Resultsmentioning

confidence: 99%

“…Cholesterol is a preferred substrate for energy production and glucogenesis by MTB 14 . Recent studies also showed the codependency of cholesterol and fatty acid metabolism for the synthesis of virulence lipids 28 . Cholesterol degradation results in the production of excess propionyl-CoA, a compound required for biosynthesis of various virulence lipids, including PDIM, and SLs 40 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features

Aiewsakun

Prombutara

Siregar

et al. 2021

Sci Rep

View full text Add to dashboard Cite

Tuberculosis is a global public health problem with emergence of multidrug-resistant infections. Previous epidemiological studies of tuberculosis in Thailand have identified a clonal outbreak multidrug-resistant strain of Mycobacterium tuberculosis in the Kanchanaburi province, designated “MKR superspreader”, and this particular strain later was found to also spread to other regions. In this study, we elucidated its biology through RNA-Seq analyses and identified a set of genes involved in cholesterol degradation to be up-regulated in the MKR during the macrophage cell infection, but not in the H37Rv reference strain. We also found that the bacterium up-regulated genes associated with the ESX-1 secretion system during its intracellular growth phase, while the H37Rv did not. All results were confirmed by qRT-PCR. Moreover, we showed that compounds previously shown to inhibit the mycobacterial ESX-1 secretion system and cholesterol utilisation, and FDA-approved drugs known to interfere with the host cholesterol transportation were able to decrease the intracellular survival of the MKR when compared to the untreated control, while not that of the H37Rv. Altogether, our findings suggested that such pathways are important for the MKR’s intracellular growth, and potentially could be targets for the discovery of new drugs against this emerging multidrug-resistant strain of M. tuberculosis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features

Aiewsakun

Prombutara

Siregar

et al. 2021

Sci Rep

View full text Add to dashboard Cite

show abstract

“…While active Mtb requires carbohydrates as the main carbon source, Mtb in a latent phase that resides within the macrophage phagolysosome, where oxygen and nutrient depletion induce a massive metabolic rearrangement [ 132 ]. Notably, several analyses of Mtb transcriptional profiles from macrophages in vitro and from the lungs of mice and humans revealed a decreased glycolysis in concert with the upregulation of Mtb genes involved in lipids catabolism, proving that fatty acid ß-oxidation, gluconeogenesis, and cholesterol are the primary carbon and energy sources during infection in macrophages [ 133 ]. Despite the importance of CCM enzymes for promoting or maintaining a persistent infection, the presence of orthologous host enzymes could prevent the election of Mtb enzymes as potential drug targets.…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

View full text Add to dashboard Cite

Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

show abstract

“…Mtb as any other bacterium is dependent on nitrogen uptake to synthesize vital biomolecules. However, Mtb has been found to prefer proteinogenic aa as the source of nitrogen over ammonium chloride when cultured in vitro [67,68]. Therefore, if the appropriate mechanisms and enzymes involved in these metabolic pathways were identified, the use of aa derived prodrugs could 'trick' Mtb to cleave off the aa and at the same time release the active form of the drug inside the cell.…”

Section: Discussionmentioning

confidence: 99%

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

et al. 2020

View full text Add to dashboard Cite

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (Mtb), each year causing millions of deaths. In this article, we present the synthesis and biological evaluations of new potential antimycobacterial compounds containing a fragment of the first-line antitubercular drug pyrazinamide (PZA), coupled with methyl or ethyl esters of selected amino acids. The antimicrobial activity was evaluated on a variety of (myco)bacterial strains, including Mtb H37Ra, M. smegmatis, M. aurum, Staphylococcus aureus, Pseudomonas aeruginosa, and fungal strains, including Candida albicans and Aspergillus flavus. Emphasis was placed on the comparison of enantiomer activities. None of the synthesized compounds showed any significant activity against fungal strains, and their antibacterial activities were also low, the best minimum inhibitory concentration (MIC) value was 31.25 µM. However, several compounds presented high activity against Mtb. Overall, higher activity was seen in derivatives containing l-amino acids. Similarly, the activity seems tied to the more lipophilic compounds. The most active derivative contained phenylglycine moiety (PC-d/l-Pgl-Me, MIC < 1.95 µg/mL). All active compounds possessed low cytotoxicity and good selectivity towards Mtb. To the best of our knowledge, this is the first study comparing the activities of the d- and l-amino acid derivatives of pyrazinamide as potential antimycobacterial compounds.

show abstract

Comparing the Metabolic Capabilities of Bacteria in the Mycobacterium tuberculosis Complex

Cited by 20 publications

References 189 publications

Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features

Transcriptional response to the host cell environment of a multidrug-resistant Mycobacterium tuberculosis clonal outbreak Beijing strain reveals its pathogenic features

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

N-Pyrazinoyl Substituted Amino Acids as Potential Antimycobacterial Agents—the Synthesis and Biological Evaluation of Enantiomers

Contact Info

Product

Resources

About