Standardization of natural mycolic acid antigen composition and production for use in biomarker antibody detection to diagnose active tuberculosis

Ndlandla, Fortunate; Ejoh, V.; Stoltz, Anton; Naicker, Brendon; Cromarty, Allan Duncan; Wyngaardt, Sandra Van; Khati, Makobetsa; Rotherham, Lia S.; Lemmer, Yolandy; Niebuhr, J.; Baumeister, C.R.; Dulayymi, Juma’a R. Al; Swai, Hulda; Baird, Mark S.; Verschoor, J.A.

doi:10.1016/j.jim.2016.05.010

Cited by 16 publications

(16 citation statements)

References 31 publications

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“…Here, two key features play a significant role; oxygenation of the MA [15][16][17][18][19][20][21][22][23], and cyclopropanation [24][25][26][27], including the specific stereochemistry of the cyclopropane ring [22][23][24][25]. Confirmation of the role of individual MA structures and benchmarked mixtures has recently been achieved through the use of synthetic derivatives [20][21][22][23][31][32][33], and strongly implies that the underlying MA structure (individually or as sugar-ester derivatives), which steers the physical properties and conformational behavior of the molecule, can offer a window to rationalize their biological role.…”

Section: Introductionmentioning

confidence: 99%

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Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

et al. 2019

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Mycobacterium tuberculosis remains a persistent pathogen, partly due to its lipid rich cell wall, of which mycolic acids (MAs) are a major component. The fluidity and conformational flexibilities of different MAs in the bacterial cell wall significantly influence its properties, function, and observed pathogenicity; thus, a proper conformational description of different MAs in different environments (e.g., in vacuum, in solution, in monolayers) can inform about their potential role in the complex setup of the bacterial cell wall. Previously, we have shown that molecular dynamics (MD) simulations of MA folding in vacuo can be used to characterize MA conformers in seven groupings relating to bending at the functional groups (W, U and Z-conformations). Providing a new OPLS-based forcefield parameterization for the critical cyclopropyl group of MAs and extensive simulations in explicit solvents (TIP4P water, hexane), we now present a more complete picture of MA folding properties together with improved simulation analysis techniques. We show that the 'WUZ' distance-based analysis can be used to pinpoint conformers with hairpin bends at the functional groups, with these conformers constituting only a fraction of accessible conformations. Applying principle component analysis (PCA) and refinement using free energy landscapes (FELs), we are able to discriminate a complete and unique set of conformational preferences for representative alpha-, methoxy-and keto-MAs, with overall preference for folded conformations. A control backbone-MA without any mero-chain functional groups showed significantly less folding in the mero-chain, confirming the role of functionalization in directing folding. Keto-MA showed the highest percentage of WUZ-type conformations and, in particular, a tendency to fold at its alpha-methyl trans-cyclopropane group, in agreement with results from Villeneuve et al. MAs demonstrate similar folding in vacuum and water, with a majority of folded conformations around the W-conformation, although the molecules are more flexible in vacuum than in water. Exchange between conformations, with a disperse distribution that includes unfolded conformers, is common in hexane for all MAs, although with more organization for Keto-MA. Globular, folded conformations are newly defined and may be specifically relevant in biofilms.

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Section: Introductionmentioning

confidence: 99%

“…MAs are central to the host immune response against the organism and have been shown to be good antigens for use in serodiagnosis of TB [30,31,[33][34][35][36]. However, fundamental details such as how MAs are arranged in the cell wall, and how they interact with immune components, are yet to be determined.…”

Section: Introductionmentioning

confidence: 99%

Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

et al. 2019

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“…For example, the detection of all three forms of MAs in bacterial extracts and gamma irradiated whole bacteria, using surface enhanced Raman spectroscopy [ 119 ]. While some studies have used a surface plasmon resonance (SPR) technique to detect serum antibodies to MAs, the method has not been validated clinically [ 120 ]. Using a biosensor platform to detect antibodies against MAs from patient serum improved MA detection (sensitivity 91.3% in TB and HIV positive patients) compared to ELISA [ 121 ].…”

Section: The Role Of “Omics” In Tb Diagnostic Developmentmentioning

confidence: 99%

Pediatric Tuberculosis: The Impact of “Omics” on Diagnostics Development

Jakhar

Bitzer

Stromberg

et al. 2020

IJMS

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Tuberculosis (TB) is a major public health concern for all ages. However, the disease presents a larger challenge in pediatric populations, partially owing to the lack of reliable diagnostic standards for the early identification of infection. Currently, there are no biomarkers that have been clinically validated for use in pediatric TB diagnosis. Identification and validation of biomarkers could provide critical information on prognosis of disease, and response to treatment. In this review, we discuss how the “omics” approach has influenced biomarker discovery and the advancement of a next generation rapid point-of-care diagnostic for TB, with special emphasis on pediatric disease. Limitations of current published studies and the barriers to their implementation into the field will be thoroughly reviewed within this article in hopes of highlighting future avenues and needs for combating the problem of pediatric tuberculosis.

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“…Natural MA mixture was isolated and single synthetic MAs synthesized as previously described (16,(36)(37)(38). The single MAs used for in vivo murine treatment in this study all contained cis-cyclopropanation, referring to the orientation of the proximal cyclopropane.…”

Section: Masmentioning

confidence: 99%

Mycolates of Mycobacterium tuberculosis modulate the flow of cholesterol for bacillary proliferation in murine macrophages

Vermeulen

Baird

Al-Dulayymi

et al. 2017

Journal of Lipid Research

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Standardization of natural mycolic acid antigen composition and production for use in biomarker antibody detection to diagnose active tuberculosis

Cited by 16 publications

References 31 publications

Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

Revealing solvent-dependent folding behavior of mycolic acids from Mycobacterium tuberculosis by advanced simulation analysis

Pediatric Tuberculosis: The Impact of “Omics” on Diagnostics Development

Mycolates of Mycobacterium tuberculosis modulate the flow of cholesterol for bacillary proliferation in murine macrophages

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