Method of screening anti-mycobacterial molecules

Abstract

This invention relates to a novel mycobacterial protein named DES, which appears to share significant amino acid sequence homology with soluble stearoyl-ACP desaturases. The results of allelic exchange experiments, indicate that the des gene may be essential to the survival of mycobacteria. These results coupled with the surface localization, the unique structure of DES, and the fact this antigen is expressed in vivo, and DES protein induces a humoral response in human patients, indicate that the DES protein provides a new target for the design of anti-mycobacterial drugs. This invention provides methods of screening molecules that can inhibit the DES enzyme activity of purified DES protein, in order to identify antibiotic molecules that are capable of inhibiting the growth or survival of mycobacteria. These methods may be practiced by using recombinant DES protein obtained from a recombinant mycobacterium host cell that was transformed with a vector containing the des gene, whose expression is controlled by regulatory or promoter sequences that function in mycobacteria. Another aspect of this invention relates to the molecules that have been identified according to the screening methods as having antibiotic activity against mycobacteria.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001] This application hereby claims the benefit under 35 U.S.C. .sctn.119(e) of U.S. provisional applications S. No. 60 / 113,375, filed Nov. 4, 1998; S. No. 60 / 111,813, filed Dec. 11, 1998; and U.S. application Ser. No. 09 / 181,934, filed Oct. 28, 1998, which was converted to a provisional application under 37 C.F.R. .sctn.1.53(c)(2)on Jan. 14, 1999. The entire disclosure of each of these applications is relied upon and incorporated by reference herein.BACKGROUND OF THE INVENTION[0002] Tuberculosis and leprosy, caused by the bacilli from the Mycobacterium tuberculosis complex and M. leprae, respectively, are the two major mycobacterial diseases. Other mycobacteriosis caused by a typical mycobacteria such as M. avium, M. xenopi, and M. Kansasii also represent major health problems worldwide.[0003] M. avium is a predominant strain isolated from T.B. patients with AIDS (Horburgh et al., 1991) and M. xenopi along with M. kansasii and M. avium, is t...

AI Technical Summary

Benefits of technology

0008] We have characterized a new M. tuberculosis exported protein named DES, identified by using the PhoA gene fusion methodology. The des gene, which seems conserved among mycobacterial species, encodes an antigenic protein highly recognized by human sera from both tuberculosis and leprosy patients but not by sera from tuberculous cattle. The results of allelic exchange experiments described in this application, indicate that the des gene is essential to the survival of mycobacteria.

Problems solved by technology

Other mycobacteriosis caused by a typical mycobacteria such as M. avium, M. xenopi, and M. Kansasii also represent major health problems worldwide.

In addition, these a typical mycobacteriosis are often difficult to cure because of the lack of efficient drugs specifically directed against a typical mycobacteria.

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