Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis

E. K. Schroeder, O. N. de Souza, D. S. Santos, John S. Blanchard, L. A. Basso

Research output: Contribution to journalArticle

119 Citations (Scopus)

Abstract

Tuberculosis resurged in the late 1980s and now kills more than 2 million people a year. The reemergence of tuberculosis as a potential public health threat, the high susceptibility of human immunodeficiency virus-infected persons to the disease, and the proliferation of multi-drug-resistant (MDR) strains have created much scientific interest in developing new antimycobacterial agents to both treat Mycobacterium tuberculosis strains resistant to existing drugs, and shorten the duration of short-course treatment to improve patient compliance. Bacterial cell-wall biosynthesis is a proven target for new antibacterial drugs. Mycolic acids, which are key components of the mycobacterial cell wall, are α-alkyl, β-hydroxy fatty acids, with a species-dependent saturated "short" arm of 20-26 carbon atoms and a "long" meromycolic acid arm of 50-60 carbon atoms. The latter arm is functionalized at regular intervals by cyclopropyl, α-methyl ketone, or α-methyl methylethers groups. The mycolic acid biosynthetic pathway has been proposed to involve five distinct stages: (i) synthesis of C20 to C26 straight-chain saturated fatty acids to provide the α-alkyl branch; (ii) synthesis of the meromycolic acid chain to provide the main carbon backbone, (iii) modification of this backbone to introduce other functional groups; (iv) the final Claisen-type condensation step followed by reduction; and (v) various mycolyltransferase processes to cellular lipids. The drugs shown to inhibit mycolic acid biosynthesis are isoniazid, ethionamide, isoxyl, thiolactomycin, and triclosan. In addition, pyrazinamide was shown to inhibit fatty acid synthase type I which, in turn, provides precursors for fatty acid elongation to long-chain mycolic acids by fatty acid synthase II. Here we review the biosynthesis of mycolic acids and the mechanism of action of antimicrobial agents that act upon this pathway. In addition, we describe molecular modeling studies on InhA, the bona-fide target for isoniazid, which should improve our understanding of the amino acid residues involved in the enzyme's mechanism of action and, accordingly, provide a rational approach to the design of new drugs.

Original languageEnglish (US)
Pages (from-to)197-225
Number of pages29
JournalCurrent Pharmaceutical Biotechnology
Volume3
Issue number3
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Mycolic Acids
Mycobacterium tuberculosis
Pharmaceutical Preparations
Fatty Acids
Carbon
Isoniazid
Cell Wall
Type I Fatty Acid Synthase
Type II Fatty Acid Synthase
Tuberculosis
Ethionamide
Triclosan
Pyrazinamide
Hydroxy Acids
Drug Design
Biosynthetic Pathways
Patient Compliance
Anti-Infective Agents
Ketones
Public Health

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Molecular Medicine
  • Biotechnology

Cite this

Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. / Schroeder, E. K.; de Souza, O. N.; Santos, D. S.; Blanchard, John S.; Basso, L. A.

In: Current Pharmaceutical Biotechnology, Vol. 3, No. 3, 2002, p. 197-225.

Research output: Contribution to journalArticle

Schroeder, E. K. ; de Souza, O. N. ; Santos, D. S. ; Blanchard, John S. ; Basso, L. A. / Drugs that inhibit mycolic acid biosynthesis in Mycobacterium tuberculosis. In: Current Pharmaceutical Biotechnology. 2002 ; Vol. 3, No. 3. pp. 197-225.
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