INHIBITION OF MYOCOLIC ACID BIOSYNTHESIS--M.TUBERCULOSIS

Project: Research project

Project Details

Description

Tuberculosis and disseminated Mycobacterium avium cause significant
morbidity and death in individuals with Human Immunodeficiency Virus
(HIV) infection. Globally, tuberculosis is a leading cause of death for
patients infected with HIV. The emergence of M. tuberculosis strains
resistant to two or more anti-tuberculosis drugs have compromised
control strategies. M. avium Complex (MAC) causes disseminated
infection and increased mortality in up to 40 percent of patients with
AIDS. There is an urgent need to develop new, potent anti-mycobacterial
drugs. Mycolic acids are integral and unique parts of the mycobacterial
cell wall and the biosynthetic enzymes represent attractive targets for
the development of novel drugs. Towards that goal, we are using a
multi-disciplinary approach employing mycobacterial genetics,
biochemistry, x-ray crystallography, molecular biology, organic
chemistry and animal models to develop novel inhibitors. We have
discovered a gene, named inhA, which was found to be a primary target
to isoniazid (INH) and ethionamide (ETH). Point mutations within the
structural gene, or overexpression of inhA confers INH- and ETH-
resistance in mycobacteria. Biochemical studies reveled that inhA
encodes an NADH-specific enoyl-acyl carrier protein (ACP) reductase
which prefers long chain fatty acids as substrates, consistent with its
role in mycolic acid biosynthesis. The three dimensional structure of
resistant and sensitive forms of InhA were determined. We demonstrated
that INH is a pro-drug which, upon activation by a catalase-peroxidase
forms a covalent adduct to NADH bound on the InhA enzyme. Armed with
the knowledge of InhA structure and function, we have generated a series
of long-chain fatty acid analog inhibitors that contain a triple bond
between C2 and C3: the 2-alkynoic acids (KOAs). The KOAs inhibit the
InhA enzyme and have activity against MAC, and against both INH-
susceptible and INH-resistant M. tuberculosis. Furthermore, we have
screened a combinatorial library of compounds against the InhA enzyme
and identified two new classes of compounds with activity against InhA
that inhibit M. tuberculosis and MAC growth. In this proposal, we
intend to expand upon these successes and continue to elucidate the key
targets of mycolic acid biosynthesis with the aim of developing novel
drugs against M. tuberculosis and M. avium.
StatusFinished
Effective start/end date7/1/984/30/09

ASJC

  • Infectious Diseases
  • Biochemistry
  • Pulmonary and Respiratory Medicine
  • Medicine(all)
  • Immunology and Microbiology(all)