Research Introduction

    Tuberculosis (TB) has long been documented in human history and still remains to be the leading cause of death from a single infectious disease today.  It was once normally curable but the emergence of multi-drug resistant tuberculosis has challenged the therapeutic practices and increased the mortality worldwide. TB infected an estimated 1.7 billion individuals worldwide with 2 to 3 million fatalities each year. TB is a highly contagious disease, which can be propelled by aerosol through coughing, spitting, or talking. TB is an opportunistic agent, which can remain latent under the protection of a waxy coat inside the macrophage for years and cause no obvious disease symptoms. Nevertheless, full-blown TB can emerge when the immune system of the infected person weakens. Cases of infection caused by multi-drug resistant Mycobacterium tuberculosis (MDR-TB) are reported through out the world. 

    The development of new drugs against Mycobacterium tuberculosis is one of the remedies urged from world health officials to combat this problem. Unfortunately, resistance has been noticed in virtually all of the available antitubercular agents, such as aminoglycosides, rifampicin, isoniazid (INH), Ethionamide, and Ethambutanol. The encroachment of MDR-TB has prompted research for new therapeutic options, for example the development of new antitubercular agents, identification of new targets for antitubercular therapy, or the study of new practices, like combination treatment, for anti-TB therapy.

    Under the protection of a distinct lipid coat like no other bacteria, which consists of layers of trehalose dimycolate (TDM), mycolylarabinogalactan, peptidoglycan, and plasma membrane, mycobacterium can remain dormant in marcophage and avoid  detection from the immune system for years.  The high lipophilicity of the lipid coat, which lowers the permeability of antitubercular agents, has been shown to be one of the causes of drug resistance.  Recent advances in the studies of the lipid envelop of TB reveals a unique structural component, 6,6'-dimycolyltrehalose (TDM), which forms the outmost layer of the bacterial membrane of TB. Three homologous proteins (ag85 A, B, and C), which possess mycolyltransferase activity, are responsible for the biosynthesis of TDM. Damage to the membranes, due to the inhibition of ag85, has been shown to increase the efficacy of antibiotics.  Therefore, ag85 represents a desirable target for the development of new antituberculosis agents. Since ag85 is a new target, no known resistance has been observed, yet.

The Lipid Cell Wall of Tuberculosis and the Structure of TDM

The principal aim in this project is to develop novel trehalose-based antitubercular agents to counteract the growing problem of multi-drug resistant Mycobacterium tuberculosis (MDR-TB). We have synthesized a library of trehalose derivatives. The leads from this library show important bacteriocidal activity. We are in the process of further optimizing the activity from the leads, and exploring the synergistic effect between our compounds and isoniazid (INH), a clinically used antitubercular agent.

We have examined our compounds against Mycobacterium smegmatis in our laboratory. We have established collaboration with two groups, Dr. Robert Reynolds at Southern Research Institute, and Dr. Raphael Chan at The Chinese University of Hong Kong, for assay against various strains of Mycobacterium tuberculosis including the MDR-TB. Dr. Czyryca, Utah State University Research Foundation, will use molecular modeling to evaluate our designs. Prof. Alan D. Elbein at University of Arkansas for Medical Science will carry out the enzymatic studies of trehalose synthase using trehalose analogs prepared in my laboratory.

(c) Enzymatic studies on the  trehalose are being conducted via collaboration.

Related Publications

(1) Hui, Y.; Chang, C.-W. T. "A Convenient Divergent Synthesis of A library of Trehalosamine Analogs." Org. Lett. 2002, 4, 2245-2248.

(2) Wang, J.; Elchert, B.; Hui, Y.; Takemoto, J. Y.; Bensaci, M.; Wennergren, J.; Chang, H.; Rai, R.; Chang, C.-W. T. “Synthesis of Trehalose-based Compounds and Study of Their Antibacterial Activity against Mycobacterium smegmatis.” Bioorg. Med. Chem. 2004, 12, 6397-6413.