Serum glutamine synthetase activity as biomarker for tuberculosis diagnosis and monitoring anti-tubercular drug therapy success

Kumar Chattopadhyay, Dipak

Abstract

Tuberculosis is a major public health problem in developing countries. It is one of the most widely spread human diseases globally. While the new diagnostics for tuberculosis (TB) have created greater interest, their full impact on global propaganda against tuberculosis is yet to be evaluated. Most of the TB cases are prevalent in the underdeveloped and developing regions of the world where the means to diagnose and to treat TB cases are limited. As a result, the infectious TB cases might remain undiagnosed or diagnosed late. So, the need of the hour is to launch a rapid but simple, inexpensive, sensitive and specific test to diagnose TB cases at the earliest. The abundant presence of glutamine synthetase (GS) in the culture filtrate of pathogenic mycobacteria has correlation with the occurrence of poly L-glutamate/glutamine component in the cell wall of these pathogenic mycobacteria but not in non-pathogenic mycobacteria. The GS seems to be stable in the infected host and also is present in host tissues and fluid. GS is demonstrated to be present in the serum of subjects suffering from pulmonary or extra-pulmonary tuberculosis; but not detectable at all in normal control and disease control (lung disease control) subjects. With anti-tubercular (A-TB) drug therapy in pulmonary and extra-pulmonary tubercular subjects, the serum GS levels fall significantly. To confirm that only the Mycobacterium tuberculosis (M. tuberculosis) GS is being assayed, the serum GS activity may be assayed in the presence of L-methionine-S, R-sulfoximine (MSO), a selective inhibitor of M. tuberculosis GS. The concentration of this inhibitor is so selected that it is sufficient to inhibit mycobacterial GS activity but not the human (mammalian) GS activity. It increases the specificity of the test. Thus, an ELISA or latex agglutination test might be inducted to assay the serum GS activity for the rapid and reliable detection of active or latent tubercular subjects and also detecting the presence of drug sensitivity or the emergence of resistance against A-TB drugs. Nevertheless, for rapid field study, the card assay technique might be implemented; where when a drop of serum from a suspected subject be placed on the substrate for GS; a definite colour change would mark the test positive. The assay for serum GS requires only a sample of serum from the patient and takes only few minutes to perform. Therefore, the results will be available instantaneously when the patient is at the medical facility centre or even at home and this will curtail the number of visits to the medical facility centre. This is really advantageous in developing and underdeveloped countries where in many cases the patients do not have the capability of making multiple visits to the medical facility centre. The test procedure can also be used as an assay to monitor the response and success of anti-tubercular drug therapy. The procedure can very well indicate whether the treatment is successful or a change in the antibiotic drug therapy would be needed.

Keyword(s)

 -glutamyl hydroxamate-Fe+3 complex; Glutamine synthetase; L-methionine-S; Pulmonary and extra- pulmonary tuberculosis; R sulfoximine; Transfer reaction

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