Anti-tuberculosis drug design based on a possible mimicry between host and pathogen lipids

Abstract

The need for new anti- TB drugs is increasingly rising because of the resistance of M. tuberculosis to existing drugs. The mycobacterial cell wall serves as an impermeable protective barrier for the bacilli from toxins and chemotherapeutic agents, mainly due to the mycolic acids waxy outer layer. The mycolic acids play an important role in the architecture and physical properties of the mycobacterial cell wall. This study was based on the observed mimicry and association between the host cholesterol and the mycolic acids. This may present yet another way in which the TB bacilli survives by manipulating its host and using some of its components for its survival. The research focused on whether the cholesterol-like molecules on the mycobacterial cell surface can be targeted for effective delivery of anti-mycobacterial agents. In order to exploit the ability of M tuberculosis to accumulate cholesterol or interact with it, a cholesterol¬binding molecule was used for targeting an anti- TB drug to the mycobacterial cell wall or to the cell membrane of infected macrophages. It was observed that the drug does possess anti-mycobacterial activities even though higher concentrations of the compound were required. This supports the idea that the ability of cholesterol to interact with the mycobacterial mycolic acids can be exploited for designing of anti- TB agents. It was also demonstrated in this study that cholesterol has a negative effect on the activity of INH. Thus cholesterol, which is required for entry and survival of M tuberculosis in the host cells, has yet another protective effect on this pathogen. The possible ability of cholesterol to target the same enzyme(s) as INH is another small piece of knowledge to complete the puzzle to understanding the mode of virulence and pathogenesis of this pathogen and develop of new ways to fight the old enemy.