scholarly journals Effect of an Oxadiazoline and a Lignan on Mycolic Acid Biosynthesis and Ultrastructural Changes ofMycobacterium tuberculosis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Eduard Baquero ◽  
Wiston Quiñones ◽  
Wellman Ribon ◽  
Maria Leonor Caldas ◽  
Ladys Sarmiento ◽  
...  
Keyword(s):  
Antimycobacterial Activity ◽  
Mycolic Acid ◽  
Mass Spectrometry Analysis ◽  
Ultrastructural Changes ◽  
Acid Biosynthesis ◽  
Spectrometry Analysis ◽  
Mycolic Acids ◽  
The World ◽  
Bacterial Morphology ◽  
Important Disease

Tuberculosis (TB) is an important disease that causes thousands of deaths around the world. Resistance against antitubercular available drugs has been reported; so, research on new effective antimycobacterial molecules is needed. Antimycobacterial activity of three lignans and two synthetic hydrazones was assessed againstMycobacterium tuberculosisH37Rv by antimycobacterial microdilution assay (TEMA). An oxadiazoline (AC451) and a lignan (ethoxycubebin) were the most active compounds (MIC 6.09 and 62.4 μM, resp.). Several changes in mycolic acid profile of treated bacteria were detected with both compounds by mass spectrometry analysis. Additionally, the level of reduction of mycolic acids in ethoxycubebin treatment was correlated to disruption in bacterial morphology.

scholarly journals Peptide sequences from the first Castoroides ohioensis skull and the utility of old museum collections for palaeoproteomics

2016 ◽  
Vol 283 (1832) ◽  
pp. 20160593 ◽  
Author(s):  
Timothy P. Cleland ◽  
Elena R. Schroeter ◽  
Robert S. Feranec ◽  
Deepak Vashishth
Keyword(s):  
Mass Spectrometry ◽  
Phylogenetic Analyses ◽  
Collagen I ◽  
Mass Spectrometry Analysis ◽  
Museum Specimens ◽  
Museum Collections ◽  
Post Translational Modifications ◽  
Spectrometry Analysis ◽  
The World

Vertebrate fossils have been collected for hundreds of years and are stored in museum collections around the world. These remains provide a readily available resource to search for preserved proteins; however, the vast majority of palaeoproteomic studies have focused on relatively recently collected bones with a well-known handling history. Here, we characterize proteins from the nasal turbinates of the first Castoroides ohioensis skull ever discovered. Collected in 1845, this is the oldest museum-curated specimen characterized using palaeoproteomic tools. Our mass spectrometry analysis detected many collagen I peptides, a peptide from haemoglobin beta, and in vivo and diagenetic post-translational modifications. Additionally, the identified collagen I sequences provide enough resolution to place C. ohioensis within Rodentia. This study illustrates the utility of archived museum specimens for both the recovery of preserved proteins and phylogenetic analyses.

scholarly journals Identification of a Stress-Induced Factor of Corynebacterineae That Is Involved in the Regulation of the Outer Membrane Lipid Composition

2009 ◽  
Vol 191 (23) ◽  
pp. 7323-7332 ◽  
Author(s):  
Xavier Meniche ◽  
Cécile Labarre ◽  
Célia de Sousa-d'Auria ◽  
Emilie Huc ◽  
Françoise Laval ◽  
...  
Keyword(s):  
Outer Membrane ◽  
Lipid Composition ◽  
Mycolic Acid ◽  
Membrane Lipid ◽  
Protein Family ◽  
Stress Conditions ◽  
Acid Biosynthesis ◽  
Membrane Lipid Composition ◽  
Mycolic Acids ◽  
Lipid Modifications

ABSTRACT Corynebacterineae are gram-positive bacteria that possess a true outer membrane composed of mycolic acids and other lipids. Little is known concerning the modulation of mycolic acid composition and content in response to changes in the bacterial environment, especially temperature variations. To address this question, we investigated the function of the Rv3802c gene, a gene conserved in Corynebacterineae and located within a gene cluster involved in mycolic acid biosynthesis. We showed that the Rv3802 ortholog is essential in Mycobacterium smegmatis, while its Corynebacterium glutamicum ortholog, NCgl2775, is not. We provided evidence that the NCgl2775 gene is transcriptionally induced under heat stress conditions, and while the corresponding protein has no detectable activity under normal growth conditions, the increase in its expression triggers an increase in mycolic acid biosynthesis concomitant with a decrease in phospholipid content. We demonstrated that these lipid modifications are part of a larger outer membrane remodeling that occurs in response to exposure to a moderately elevated temperature (42°C). In addition to showing an increase in the ratio of saturated corynomycolates to unsaturated corynomycolates, our results strongly suggested that the balance between mycolic acids and phospholipids is modified inside the outer membrane following a heat challenge. Furthermore, we showed that these lipid modifications help the bacteria to protect against heat damage. The NCgl2775 protein and its orthologs thus appear to be a protein family that plays a role in the regulation of the outer membrane lipid composition of Corynebacterineae under stress conditions. We therefore propose to name this protein family the envelope lipids regulation factor (ElrF) family.

scholarly journals Antimycobacterial Activity and Mechanism of Action of NAS-91

2007 ◽  
Vol 52 (3) ◽  
pp. 1162-1166 ◽  
Author(s):  
Paul Gratraud ◽  
Namita Surolia ◽  
Gurdyal S. Besra ◽  
Avadhesha Surolia ◽  
Laurent Kremer
Keyword(s):  
Oleic Acid ◽  
Mechanism Of Action ◽  
Desaturase Activity ◽  
Antimycobacterial Activity ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Antimalarial Agents ◽  
Direct Demonstration ◽  
Δ9 Desaturase ◽  
A Cell

ABSTRACT The antimalarial agents NAS-91 and NAS-21 were found to express potent antimycobacterial activity, NAS-91 being more active than NAS-21. They partially inhibited mycolic acid biosynthesis and profoundly altered oleic acid production. The development of a cell-free assay for Δ9-desaturase activity allowed direct demonstration of the inhibition of oleic acid biosynthesis by these compounds.

scholarly journals Phylogenomic Reappraisal of Fatty Acid Biosynthesis, Mycolic Acid Biosynthesis and Clinical Relevance Among Members of the Genus Corynebacterium

2021 ◽  
Vol 12 ◽  
Author(s):  
Lynn G. Dover ◽  
Amy R. Thompson ◽  
Iain C. Sutcliffe ◽  
Vartul Sangal
Keyword(s):  
Fatty Acid ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Cell Envelope ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Pathogenic Potential ◽  
Mycolic Acids ◽  
Key Genes ◽  
Cell Envelopes

The genus Corynebacterium encompasses many species of biotechnological, medical or veterinary significance. An important characteristic of this genus is the presence of mycolic acids in their cell envelopes, which form the basis of a protective outer membrane (mycomembrane). Mycolic acids in the cell envelope of Mycobacterium tuberculosis have been associated with virulence. In this study, we have analysed the genomes of 140 corynebacterial strains, including representatives of 126 different species. More than 50% of these strains were isolated from clinical material from humans or animals, highlighting the true scale of pathogenic potential within the genus. Phylogenomically, these species are very diverse and have been organised into 19 groups and 30 singleton strains. We find that a substantial number of corynebacteria lack FAS-I, i.e., have no capability for de novo fatty acid biosynthesis and must obtain fatty acids from their habitat; this appears to explain the well-known lipophilic phenotype of some species. In most species, key genes associated with the condensation and maturation of mycolic acids are present, consistent with the reports of mycolic acids in their species descriptions. Conversely, species reported to lack mycolic acids lacked these key genes. Interestingly, Corynebacterium ciconiae, which is reported to lack mycolic acids, appears to possess all genes required for mycolic acid biosynthesis. We suggest that although a mycolic acid-based mycomembrane is widely considered to be the target for interventions by the immune system and chemotherapeutics, the structure is not essential in corynebacteria and is not a prerequisite for pathogenicity or colonisation of animal hosts.

scholarly journals Determination of the primary target for isoniazid in mycobacterial mycolic acid biosynthesis with Mycobacterium aurum A+

1996 ◽  
Vol 318 (2) ◽  
pp. 451-457 ◽  
Author(s):  
Paul R WHEELER ◽  
Paul M ANDERSON
Keyword(s):  
Cell Wall ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Biosynthetic Activity ◽  
Minimum Concentration ◽  
Mycolic Acids ◽  
Cell Wall Preparation ◽  
Hydroxylated Fatty Acids ◽  
Mycobacterium Aurum

The target of the potent antituberculosis drug isoniazid was investigated in Mycobacterium aurum A+, against which isoniazid has an MIC (the minimum concentration required to give growth inhibition) of 0.3 µg/ml. Mycolic acid biosynthesis, measured by the incorporation of label from [1-14C]acetate into mycolic acids, was inhibited differentially by isoniazid in cell-wall preparations of M. aurum A+. Thus at an isoniazid concentration of 1 µg/ml, mycolic acid biosynthesis was inhibited by 80% but concomitant biosynthesis of non-hydroxylated fatty acids was inhibited by only 15%. Three lines of evidence identified 24:1 cis-5 elongase as the primary isoniazid target. First, 24:1 cis-5 did not restore isoniazid-inhibited mycolic acid biosynthetic activity in a crude cell-wall preparation, suggesting that the drug acts after the formation of the Δ-5 double bond. Secondly, a 24:1 cis-5 elongase assay in which the product is mycolic acid is completely inhibited by isoniazid. Finally, the only intermediates that accumulate as a result of the addition of isoniazid are acids of 24 carbons. Both 24:0 and 24:1 are observed in a similar ratio whether or not isoniazid is present, even though concomitant mycolic acid biosynthesis is inhibited by isoniazid. These results are consistent with studies of the M. tuberculosis InhA protein by Dessen, Quemard, Blanchard, Jacobs and Sacchettini [(1995) Science 267, 1638–1641].

scholarly journals ACCase 6 is the essential acetyl-CoA carboxylase involved in fatty acid and mycolic acid biosynthesis in mycobacteria

Microbiology ◽  
2009 ◽  
Vol 155 (8) ◽  
pp. 2664-2675 ◽  
Author(s):  
Daniel G. Kurth ◽  
Gabriela M. Gago ◽  
Agustina de la Iglesia ◽  
Bernardo Bazet Lyonnet ◽  
Ting-Wan Lin ◽  
...  
Keyword(s):  
Fatty Acid ◽  
Active Sites ◽  
Fatty Acid Synthase ◽  
Fatty Acid Biosynthesis ◽  
De Novo ◽  
Building Blocks ◽  
Mycolic Acid ◽  
Acid Biosynthesis ◽  
Minimal Inhibitory Concentrations ◽  
Mycolic Acids

Mycolic acids are essential for the survival, virulence and antibiotic resistance of the human pathogen Mycobacterium tuberculosis. Inhibitors of mycolic acid biosynthesis, such as isoniazid and ethionamide, have been used as efficient drugs for the treatment of tuberculosis. However, the increase in cases of multidrug-resistant tuberculosis has prompted a search for new targets and agents that could also affect synthesis of mycolic acids. In mycobacteria, the acyl-CoA carboxylases (ACCases) provide the building blocks for de novo fatty acid biosynthesis by fatty acid synthase (FAS) I and for the elongation of FAS I products by the FAS II complex to produce meromycolic acids. By generating a conditional mutant in the accD6 gene of Mycobacterium smegmatis, we demonstrated that AccD6 is the essential carboxyltransferase component of the ACCase 6 enzyme complex implicated in the biosynthesis of malonyl-CoA, the substrate of the two FAS enzymes of Mycobacterium species. Based on the conserved structure of the AccD5 and AccD6 active sites we screened several inhibitors of AccD5 as potential inhibitors of AccD6 and found that the ligand NCI-172033 was capable of inhibiting AccD6 with an IC50 of 8 μM. The compound showed bactericidal activity against several pathogenic Mycobacterium species by producing a strong inhibition of both fatty acid and mycolic acid biosynthesis at minimal inhibitory concentrations. Overexpression of accD6 in M. smegmatis conferred resistance to NCI-172033, confirming AccD6 as the main target of the inhibitor. These results define the biological role of a key ACCase in the biosynthesis of membrane and cell envelope fatty acids, and provide a new target, AccD6, for rational development of novel anti-mycobacterial drugs.

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