Isoniazid (INH), a bactericidal drug showing specific activity against M.tb, is part of the first-line drug combination regimen for antitubercular therapy. INH is activated within the mycobacterial cell by the KatG catalase. The activated form is thought to suppress mycolic acid biosynthesis through the inhibition of InhA, an enzyme involved in fatty acid synthesis. InhA is thus one of the best validated targets in the treatment of tuberculosis (TB). It is anticipated that a drug directly targeting InhA in a different location than activated INH and not requiring activation by KatG may have bactericidal and sterilizing properties superior to those of INH. As most INH resistance is mediated through mutations in katG, there also should be very little if any cross resistance between a direct inhibitor of InhA and INH.   

 The objective of this program is to identify such an InhA inhibitor as a potential new first line agent against active tuberculosis. A compound of this type could also replace INH as an early bactericidal agent that significantly reduces bacterial load in the intensive phase of treatment, in a completely new drug combination for TB therapy. This novel agent should be orally administered, well tolerated, and show a low propensity to generate resistance.