2011
DOI: 10.1128/aac.00266-11
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Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Abstract: Drug resistance in Mycobacterium tuberculosis has become a serious global health threat, which is now complicated by the emergence of extensively drug-resistant strains. New drugs that are active against drugresistant tuberculosis (TB) are needed. We chose to search for new inhibitors of the enoyl-acyl carrier protein (ACP) reductase InhA, the target of the first-line TB drug isoniazid (also known as isonicotinoic acid hydrazide [INH]). A subset of a chemical library, composed of 300 compounds inhibiting Plasm… Show more

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Cited by 61 publications
(53 citation statements)
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“…This type of approach has been used extensively to rationally optimize inhibitors of the FAS-II elongation cycle-in particular, analogs of thiolactomycin as inhibitors of KasA/ KasB and triclosan derivatives as inhibitors of InhA (Pan and Tonge 2012). The screening of inhibitors showing activity against the Plasmodium falciparum enoyl reductase and bhydroxyacyl-ACP dehydratase, FabZ, identified compounds that appear to target the corresponding FAS-II enzymes in Mtb and display an MIC against whole mycobacterial cells (Bhowruth et al 2008;Gratraud et al 2008;Vilchèze et al 2011). Pyridomycin, a cyclic depsipeptide isolated from Streptomyces with an MIC value of 0.4 mg/mL against Mtb, is now known to also target InhA (Haatkoorn et al 2012), as are novel structural classes of inhibitors in the lead-optimization phase reported by the Working Group on New TB Drugs (Table 1).…”
Section: Drugs Targeting Mycolic Acid Biosynthesis and Exportmentioning
confidence: 99%
“…This type of approach has been used extensively to rationally optimize inhibitors of the FAS-II elongation cycle-in particular, analogs of thiolactomycin as inhibitors of KasA/ KasB and triclosan derivatives as inhibitors of InhA (Pan and Tonge 2012). The screening of inhibitors showing activity against the Plasmodium falciparum enoyl reductase and bhydroxyacyl-ACP dehydratase, FabZ, identified compounds that appear to target the corresponding FAS-II enzymes in Mtb and display an MIC against whole mycobacterial cells (Bhowruth et al 2008;Gratraud et al 2008;Vilchèze et al 2011). Pyridomycin, a cyclic depsipeptide isolated from Streptomyces with an MIC value of 0.4 mg/mL against Mtb, is now known to also target InhA (Haatkoorn et al 2012), as are novel structural classes of inhibitors in the lead-optimization phase reported by the Working Group on New TB Drugs (Table 1).…”
Section: Drugs Targeting Mycolic Acid Biosynthesis and Exportmentioning
confidence: 99%
“…Because resistance to INH is on the rise worldwide, with an estimated 13% of tuberculosis cases exhibiting resistance to this important drug, its long-term utility may be limited. As a result, significant effort has been directed toward identifying novel inhibitors of InhA (12)(13)(14), including an effort by Glaxo-Smith Kline and the TB Alliance. Identification of a drug that targets the critical pathway of mycolic acid biosynthesis at a step that is distinct from InhA, thereby bypassing INH resistance, would have a major impact on treatment of MDR and XDR tuberculosis.…”
mentioning
confidence: 99%
“…Indeed, studies seem to bear out this rationale [20,21]. Therefore, to minimize the probability of a single mutation leading to resistance, we have argued elsewhere [4] that it may be beneficial to target multiple enzymes representing metabolic "hubs" which are essential for multiple biosynthetic pathways involved in mycobacterium cell wall synthesis.…”
Section: Design Of Boronic-auronesmentioning
confidence: 99%