Differential spontaneous folding of mycolic acids from Mycobacterium tuberculosis

AbstractMycolic acids are structural components of the mycobacterial cell wall that have been implicated in the pathogenicity and drug resistance of certain mycobacterial species. They also offer potential in areas such as rapid serodiagnosis of human and animal tuberculosis. It is increasingly recognized that conformational behavior of mycolic acids is very important in understanding all aspects of their function. Atomistic molecular dynamics simulations, in vacuo, of stereochemically defined Mycobacterium tuberculosis mycolic acids show that they fold spontaneously into reproducible conformational groupings. One of the three characteristic mycolate types, the keto-mycolic acids, behaves very differently from either α-mycolic acids or methoxy-mycolic acids, suggesting a distinct biological role. However, subtle conformational behavioral differences between all the three mycolic acid types indicate that cooperative interplay of individual mycolic acids may be important in the biophysical properties of the mycobacterial cell envelope and therefore in pathogenicity

Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop

The antigenicity and cholesteroid nature of mycolic acids determined by recombinant chicken antibodies

<div><p>Mycolic acids (MA) are major, species-specific lipid components of Mycobacteria and related genera. In <i>Mycobacterium tuberculosis</i>, it is made up of alpha-, methoxy- and keto-MA, each with specific biological functions and conformational characteristics. Antibodies in tuberculosis (TB) patient sera respond differently towards the three MA classes and were reported to cross-react with cholesterol. To understand the antigenicity and cholesterol cross-reactivity of MA, we generated three different chicken -derived phage-displayed single-chain variable fragments (scFv) that reacted similarly towards the natural mixture of MA, but the first recognized all three classes of chemically synthetic MAs, the second only the two oxygenated types of MAs and the third only methoxy MA. The cholesterol cross-reactivity was investigated after grafting each of the three scFv types onto two configurations of constant chain domains–CH1-4 and CH2-4. Weak but significant cross-reactivity with cholesterol was found only with CH2-4 versions, notably those two that were also able to recognize the <i>trans</i>-keto MA. The cholesteroid nature of mycobacterial mycolic acids therefore seems to be determined by the <i>trans</i>-keto MA subclass. The significantly weaker binding to cholesterol in comparison to MA confirms the potential TB diagnostic application of these antibodies.</p></div

Elevated serum antibody responses to synthetic mycobacterial lipid antigens among UK farmers: an indication of exposure to environmental mycobacteria?

Background: mycobacterial cells contain complex mixtures of mycolic acid esters. These can be used as antigens recognised by antibodies in the serum of individuals with active tuberculosis, caused by Mycobacterium tuberculosis. In high burden populations, a significant number of false positives are observed; possibly these antigens are also recognised by antibodies generated by other mycobacterial infections, particularly ubiquitous ‘environmental mycobacteria’. This suggests similar responses may be observed in a low burden TB population, particularly in groups regularly exposed to mycobacteria. Methods: ELISA using single synthetic trehalose mycolates corresponding to major classes in many mycobacteria was used to detect antibodies in serum of individuals with no known mycobacterial infection, comprising farmers, abattoir workers, and rural and urban populations. Results: serum from four Welsh or Scottish cohorts showed lower (with some antigens significantly lower) median responses than those reported for TB negatives from high-burden TB populations, and significantly lower responses than those with active TB. A small fraction, particularly older farmers, showed strong responses. A second study examined BCG vaccinated and non-vaccinated farmers and non-farmers. Farmers gave significantly higher median responses than non-farmers with three of five antigens, while there was no significant difference between vaccinated or non-vaccinated for either farmer or non-farmer groups. Conclusions: this initial study shows that serodiagnosis with mycobacterial lipid antigens can detect antibodies in a population sub-group that is significantly exposed to mycobacteria, in an assay that is not interfered with by vaccination. Given the links between mycobacterial exposure and a range of immune system diseases, further understanding such responses may provide a new opportunity for monitoring public health and directing treatment

The first syntheses of single enantiomers of the major methoxymycolic acid of Mycobacterium tuberculosis

Mycolic acids (Scheme 1) are major constituents of the cell envelope of Mycobacterium tuberculosis and other mycobacteria, some of which are pathogenic to animals and humans.1 and 2 Their presence is thought to be linked with the resistance of these organisms to most current antibiotics and other chemotherapeutic agents.3 Mycolic acids can be divided into two parts, meromycolate and mycolic motif (Scheme 1). The latter is common to each mycobacterial mycolic acid, except for minor variations in the length of the chain(d)We thank Prof. D. E. Minnikin (Univ. of Birmingham) for providing a sample of natural methoxymycolic acid extracted from M. tuberculosis

What is the potential for context aware communication aids?

Use of voice output communication aids (VOCAs) can be a very effective strategy to assist people with speech impairments in communicating. Despite this, people who use communication aids often express frustration with VOCAs—desiring devices that are simpler, quicker and more effective to use. Whilst it is not possible to resolve all these issues with technology, it is argued that significant progress can be made. The use of contextual information is one development that could improve the simplicity and effectiveness of communication aid design. Improving the effectiveness of communication aids, including through the use of context support, is a goal of the NIHR Devices for Dignity Assistive Technology Theme. This discussion paper examines the potential for creating ‘context aware’ communication aids. Three projects in which the authors have been involved are described to illustrate different approaches to the use of contextual information