Mycolic acids and their trehalose esters are very important components of mycobacterial cells. They show many biological effects and can be used to detect infection by diseases such as tuberculosis. In this project, a variety of novel trehalose esters of mycolic acids (TDM and TMM) were synthesised for use as antigens and to study their effects on the immune system.
The project which the thesis describes consisted of five parts:
In the first part, a series of six novel cord factors were prepared by coupling synthetic keto, hydroxyl- and methoxy-mycolic acids containing both cis- and trans-cyclopropanes with protected trehalose. These compounds were synthesised in order to ascertain their efficacy as antigens in ELISA assays to detect active TB in serum samples. These assays showed that trehalose dimycolate A provided a better distinction than natural TDM from
Mycobacterium tuberculosis.
Preliminary results show that some of these compounds also strongly stimulate the production ofTNFa, IL-6 and IL-IP in cell line assays.
The second part comprised the synthesis of saturated P-hydroxy acids, models for mycolic acids, without cyclopropane and functional groups, thereby completing the preparation of three saturated cord factors.
The third part involved the preparation of four trehalose esters from simple fatty acids.
The fourth part involved the synthesis of a novel a-methyl-trans-alkene keto-mycolic acid present in M tuberculosis and in other mycobacteria.
Finally, the fifth part entailed the preparation of different types of esters based on the N-acetylmuramic acid core, including those from simple long-chain acids, and from complete synthetic mycolic acids, such as compound B.
These compounds could then be utilised to study the immunological properties of synthetic analogs of muramyl dipeptide, which would then allow for the detennination of those structural features which are responsible for adjuvant action.