<i>inhA</i>
            , a Gene Encoding a Target for Isoniazid and Ethionamide in
            <i>Mycobacterium tuberculosis</i>

Banerjee, Asesh; Dubnau, Eugenie; Quémard, Annaık̈; Balasubramanian, V.; Um, Kyung Sun; Wilson, Theresa; Collins, Desmond M.; Lisle, Geoffrey de; Jacobs, William R.

doi:10.1126/science.8284673

Cited by 1,293 publications

(998 citation statements)

References 30 publications

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“…In summary, the above CFM measurements provide direct, unambiguous confirmation that mycolic acids confer strong hydrophobic properties to the cells and that these properties are lost after treatment with antimycobacterial drugs. [2]. For EMB, this finding is more surprising because the drug inhibits the polymerization of arabinose found in arabinogalactan and LAM [4].…”

Section: Structural Changes Correlate With Differences In Chemical Prmentioning

confidence: 99%

“…Ethionamide (ETH) and isoniazid (INH) inhibit the enoyl ACP reductase InhA involved in the biosynthesis of mycolic acids [2], while the synthesis of the glycosylated portion of the wall is efficiently inhibited by ethambutol (EMB), which targets arabinosyltransferases [4]. Streptomycin (STR) targets the 30S subunit of ribosomes, leading to an inhibition of protein synthesis [30].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Organization of the mycobacterial cell wall: a nanoscale view

Alsteens

Verbelen

Dague

et al. 2007

Pflugers Arch - Eur J Physiol

109

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The biosynthesis of the Mycobacterium tuberculosis cell wall is targeted by some of the most powerful antituberculous drugs. To date, the molecular mechanisms by which these antibiotics affect the cell wall characteristics are not well understood. Here, we used atomic force microscopy -in three different modes -to probe the nanoscale surface properties of live mycobacteria and their modifications upon incubation with four antimycobacterial drugs: isoniazid, ethionamide, ethambutol, and streptomycine. Topographic imaging, combined with quantitative surface roughness analysis, demonstrated that all drugs induce a substantial increase of surface roughness to an extent that correlates with the localization of the target (i.e., synthesis of mycolic acids, arabinogalactans, or proteins). Chemical force microscopy with hydrophobic tips revealed that the structural alterations induced by isoniazid and ethambutol were correlated with a dramatic decrease of cell surface hydrophobicity, reflecting the removal of the outermost mycolic acid layer. Consistent with this finding, tapping mode imaging, combined with immunogold labeling, showed that the two drugs lead to the massive exposure of hydrophilic lipoarabinomannans at the surface. Taken together, these structural, chemical, and immunological data provide novel insight into the action mode of antimycobacterial drugs, as well as into the spatial organization of the mycobacterial cell wall.

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Section: Structural Changes Correlate With Differences In Chemical Prmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Organization of the mycobacterial cell wall: a nanoscale view

Alsteens

Verbelen

Dague

et al. 2007

Pflugers Arch - Eur J Physiol

109

View full text Add to dashboard Cite

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“…10 The product of the M. tuberculosis inhA gene (InhA) has been shown to be a major target for isoniazid (INH, isonicotinic acid hydrazide), the most prescribed drug for active TB infection and prophylaxis. 12 InhA was identified as an NADH-dependent enoyl-ACP (acyl carrier protein) reductase enzyme, which exhibits specificity for long-chain (C 18 > C 16 ) enoyl thioester substrates. 13 InhA is a member of the mycobacterial FAS-II system, which elongates acyl fatty acid precursors yielding the long carbon chain of the meromycolate branch of mycolic acids, the hallmark of mycobacteria.…”

Section: Introductionmentioning

confidence: 99%

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Basso¹,

Schneider²,

Santos³

et al. 2010

J. Braz. Chem. Soc.

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Descrevemos a atividade inibitória do IQG607, pentaciano(isoniazida)ferrato(II), frente a cepas de Mycobacterium tuberculosis tanto resistentes quanto sensíveis à isoniazida, assim como a toxicidade oral e a adaptação da síntese química do IQG607 para reatores maiores. O IQG607 representa um potencial agente quimioterápico que inibe um alvo molecular definido.Here we describe the inhibitory activity of IQG607, pentacyano(isoniazid)ferrate(II), on isoniazid-sensitive and isoniazid-resistant strains of Mycobacterium tuberculosis, its oral toxicity, and efforts to adapt IQG607 synthesis to large chemical reactors. IQG607 represents a promising chemotherapeutic agent aiming at the inhibition of a validated and druggable molecular target. Keywords: Mycobacterium tuberculosis, enoyl reductase, toxicology, large-scale synthesis, metallodrug IntroductionTuberculosis (TB) remains the leading cause of mortality due to a bacterial pathogen, Mycobacterium tuberculosis. 1 In 2007, there were an estimated 9.27 million cases of TB, and 1.37 million (15%) were also HIV-positive patients, who are more likely to develop active TB. 2 Brazil ranks 14 th in terms of the total number of incident cases amongst the high-burden countries. 2 There were an estimated 0.5 million cases of multidrugresistant TB (MDR-TB), which is caused by strains resistant to, at least, isoniazid and rifampicin. 2 The emergence of extensively drug-resistant (XDR) TB cases, which are found in TB-infected patients whose isolates are MDR and also resistant to a fluoroquinolone and, at least, one second-line injectable agent, 2,3 its widespread distribution, 4 and unprecedented fatality rate, 5 raise the prospect of virtually incurable and deadly TB worldwide. The factors that most influence the emergence of drugresistant strains include inappropriate treatment regimens and patient noncompliance in completing the prescribed courses of therapy due to the lengthy standard "shortcourse" treatment (isoniazid, rifampicin, pyrazinamide, and ethambutol or streptomycin for two months, followed by a combination of isoniazid and rifampicin for additional four months) or when the side effects become unbearable. 6 Moreover, no sustainable control of TB epidemic can be reached in any country without properly addressing this global public health problem, including research as a key component. 7 M. tuberculosis has been considered the world's most successful pathogen, and this is largely due to the ability of the bacillum to persist in host tissues, where drugs that are rapidly bactericidal in vitro require prolonged administration to achieve comparable in vivo effects. 8 Hence, more effective and less toxic anti-tubercular agents are immediately needed to shorten the duration of current treatment, improve the treatment of drug-resistant TB, and to provide effective treatment of latent TB infection.The modern approach in the development of new chemical entities (NCEs) against TB is based on the use of defined molecular targets. This involves (i) the search and identification ...

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“…6 Moreover, we have identified the molecular target of 1 as the mycobacterial NADH-dependent enoyl-[acyl-carrierprotein] reductase (InhA), 6 which is also the target of the clinical TB drug isoniazid (INH) (after metabolic activation and formation of a NADH adduct as the effective inhibitory species). 7,8 Pyridomycin (1) is a competitive inhibitor at the NADH-binding site of InhA but has not shown cross-resistance with INH. 6 This suggests that the exact molecular interactions of 1 with the NADH-binding site differ from those of the NADH adduct of INH.…”

mentioning

confidence: 99%

Synthesis and Antimycobacterial Activity of 2,1′-Dihydropyridomycins

Horlacher

Hartkoorn

Cole

et al. 2012

ACS Med. Chem. Lett.

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Dihydropyridomycins 2 and 3, which lack the characteristic enol ester moiety of the potent antimycobacterial natural product pyridomycin (1), have been prepared from L-Thr, R-and S-hydroxy isovaleric acid, and 3-pyridinecarboxaldehyde. The 2R isomer 2 shows only 4-fold lower anti-Mtb activity than 1, indicating that the enol ester moiety in the natural product is not critical for its biological activity. This finding establishes 2 as a potent and more practical lead for anti-TB drug discovery.KEYWORDS: natural products, InhA, pyridomycin, total synthesis, tuberculosis T uberculosis (TB) is a frequently fatal infectious disease that causes more than 1.4 million deaths annually. TB was considered to be well contained in the 1960s, but recent decades have witnessed a resurgence of the disease, even in industrialized countries, due to comorbidity with AIDS and the emergence of multi-and extensively drug-resistant (MDR, XDR) strains of the causative pathogen Mycobacterium tuberculosis (Mtb). 1 These developments were paralleled by a decline in TB-directed drug discovery efforts; thus, as of today, the last TB drug with a novel mode of action was launched more than 40 years ago, and current combination therapy is insufficient to eliminate XDR Mtb. 2 As a consequence, there is an urgent need for the development of new anti-TB agents that can shorten the duration of treatment (current standard first line therapy of TB extends over 6 months) and/or are active against MDR and XDR bacteria.Pyridomycin (1) (Chart 1) is a bacterial natural product that was first isolated from the Streptomyces strain 6706 in 1953. 3,4 The compound was subsequently shown to exhibit significant in vitro antimycobacterial activity and low systemic toxicity in mice. 5 While these findings were not further explored for decades to come, we have recently confirmed the in vitro antimycobacterial activity of 1, which we found to inhibit Mtb growth with a minimal inhibitory concentration (MIC) of 0.3 μg/mL. 6 Moreover, we have identified the molecular target of 1 as the mycobacterial NADH-dependent enoyl-[acyl-carrierprotein] reductase (InhA), 6 which is also the target of the clinical TB drug isoniazid (INH) (after metabolic activation and formation of a NADH adduct as the effective inhibitory species). 7,8 Pyridomycin (1) is a competitive inhibitor at the NADH-binding site of InhA but has not shown cross-resistance with INH. 6 This suggests that the exact molecular interactions of 1 with the NADH-binding site differ from those of the NADH adduct of INH. Together with the fact that the structure of 1 does not resemble any known TB drug, these findings render pyridomycin an auspicious starting point for TB drug discovery.Only a single total synthesis of 1 has been reported in the literature; significant difficulties were encountered in that work 9 with regard to the establishment of the enol ester double bond between C2 and C1′, 10 a problem that could not be solved in a fully satisfactory manner. In light of these difficulties, we felt th...

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inhA , a Gene Encoding a Target for Isoniazid and Ethionamide in Mycobacterium tuberculosis

Cited by 1,293 publications

References 30 publications

Organization of the mycobacterial cell wall: a nanoscale view

Organization of the mycobacterial cell wall: a nanoscale view

An inorganic complex that inhibits Mycobacterium tuberculosis enoyl reductase as a prototype of a new class of chemotherapeutic agents to treat tuberculosis

Synthesis and Antimycobacterial Activity of 2,1′-Dihydropyridomycins

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