Investigational Thiophene Drug Kills Tuberculosis Bacteria by Blocking Mycolic Acid Synthesis

An experimental drug prevents growth of the tuberculosis (TB)-causing bacterium, Mycobacterium tuberculosis (Mtb), by blocking the metabolic pathway for synthesis of mycolic acid, which is an essential component of the organism's cell membrane.

The cell envelope of M. tuberculosis is distinctive and is associated with its pathogenicity. Features that are very prominent in the cell envelope are the presence of arabinogalactan-mycolate covalently linked to the cell wall peptidoglycan via a phosphodiester bond located on the inner leaflet of the outer membrane and of a free glycolipid called trehalose dimycolate (TDM), which accumulates in a cord-like fashion on the surface of the cells. This provides a thick layer of lipid on the outer part of the cell and protects the tubercle bacillus from noxious chemicals and the host's immune system. Mycolic acids are the major constituents of this protective layer. They also play other important roles as structural components of the cell wall and envelope. More specifically, the cyclopropane rings in mycolic acids of Mtb contribute to the structural integrity of the cell wall complex and protect the bacillus from oxidative stress (hydrogen peroxide).
Investigators at the University of Medicine and Dentistry of New Jersey (Newark, USA) described a new class of thiophene compounds that killed Mtb by the previously uncharacterized mechanism of Pks13 (polyketide synthase 13) inhibition. The Pks13 enzyme catalyzes the condensation of two fatty acyl chains in the final steps of mycolic acid biosynthesis. Thiophenes are important heterocyclic compounds that are widely employed as building blocks in many agriculture and pharmaceuticals chemicals.

Results reported in the June 16, 2013, online edition of the journal Nature Chemical Biology revealed that treatment of Mtb cultures with an experimental thiophene drug was bactericidal and equivalent to treatment with the first-line drug isoniazid, but was less likely to permit emergent resistance. Combined isoniazid and thiophene treatment resulted in complete inhibition of Mtb growth.

“Mtb is a little ball of soap,” said senior author Dr. David Alland, professor of medicine at the University of Medicine and Dentistry of New Jersey. “This study confirms that M. tuberculosis Pks13 is required for mycolic acid biosynthesis, validates it as a druggable target, and demonstrates the therapeutic potential of simultaneously inhibiting multiple targets in the same biosynthetic pathway.”

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University of Medicine and Dentistry of New Jersey