High Affinity InhA Inhibitors with Activity against Drug-Resistant Strains of <i>Mycobacterium tuberculosis</i>

Sullivan, T. E.; Truglio, J.J.; Boyne, Melissa E.; Novichenok, Polina; Zhang, Xujie; Stratton, Christopher F.; Li, Huei-Jiun; Kaur, Tejinder; Amin, Amol; Johnson, Francis; Slayden, Richard A.; Kisker, Caroline; Tonge, Peter J.

doi:10.1021/cb0500042

Cited by 235 publications

(279 citation statements)

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“…The inhA gene is essential in mycobacteria, and inhibition of InhA enzymatic activity leads to mycobacterial cell death (39). InhA, as a drug target, has been validated by several studies (5,9,20,24,33,36). GlaxoSmithKline and the TB Alliance have conducted an InhA target-based screen of a million compounds and are in the lead optimization phase (http://www.tballiance.org/new /portfolio/html-portfolio-item.php?idϭ5).…”

mentioning

confidence: 99%

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Vilchèze

Baughn

Tufariello

et al. 2011

Antimicrob Agents Chemother

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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 Plasmodium falciparum enoyl reductase, was tested against M. tuberculosis. Four compounds were found to inhibit M. tuberculosis growth with MICs ranging from 1 M to 10 M. Testing of these compounds against M. tuberculosis in vitro revealed that only two compounds (CD39 and CD117) were bactericidal against drug-susceptible and drug-resistant M. tuberculosis. These two compounds were also bactericidal against M. tuberculosis incubated under anaerobic conditions. Furthermore, CD39 and CD117 exhibited increased bactericidal activity when used in combination with INH or rifampin, but CD39 was shown to be toxic to eukaryotic cells. The compounds inhibit InhA as well the fatty acid synthase type I, and CD117 was found to also inhibit tuberculostearic acid synthesis. This study provides the TB drug development community with two chemical scaffolds that are suitable for structureactivity relationship study to improve on their cytotoxicities and bactericidal activities in vitro and in vivo.The fight against tuberculosis (TB), a disease caused by the bacillus Mycobacterium tuberculosis, is facing new challenges with the surge of multidrug-resistant (MDR) TB and the recent emergence of extensively drug-resistant (XDR) TB (8). TB strains resistant to the first-line anti-TB drugs (FLDs) isoniazid (also known as isonicotinoic acid hydrazide [INH]) and rifampin (RIF) are classified as MDR-TB, while XDR-TB is defined as MDR-TB resistant to any fluoroquinolone and one or more of the three injectable drugs (6). The need for novel TB drugs has spurred a new interest in TB drug development, and several new TB drugs are currently being tested in clinical trials (18). Nevertheless, expanding the pharmacopeia of active TB drugs remains an important goal, as M. tuberculosis has proven to be more than adept at acquiring drug resistance. One strategy to develop new drugs effective against MDR-and XDR-TB is to target essential functions that are not aims of the current anti-TB drug regimen. An alternative is to develop new drugs with novel requirements for inhibition of a bona fide target, with the goal of circumventing extant drug resistance.TB is resistant to most commonly used antibacterial agents due in part to its unusual cell wall structure. The mycobacterial cell wall contains unique long-chain (C 70 to C 90 ), ␣-alkyl, ␤-hydroxy fatty acids called mycolic acids. The synthesis of these fatty acids requires the coenzyme A (CoA)-dependent fatty acid synthase type I (FASI) and the acyl carrier protein (ACP)-dependent multienzyme fatty ...

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confidence: 99%

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Vilchèze

Baughn

Tufariello

et al. 2011

Antimicrob Agents Chemother

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“…Two groups have recently published work describing 5-substituted triclosan analogs (16,25). Sullivan et al (25) reported 5-alkyl-substituted triclosan derivatives assayed against Mycobacterium tuberculosis enoyl acyl ACP reductase (InhA) that did not feature chlorine substitution on the B-ring.…”

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confidence: 99%

X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy

Freundlich

Wang

Tsai

et al. 2007

Journal of Biological Chemistry

115

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The x-ray crystal structures of five triclosan analogs, in addition to that of the isoniazid-NAD adduct, are described in relation to their integral role in the design of potent inhibitors of the malarial enzyme Plasmodium falciparum enoyl acyl carrier protein reductase (PfENR). Many of the novel 5-substituted analogs exhibit low micromolar potency against in vitro cultures of drug-resistant and drug-sensitive strains of the P. falciparum parasite and inhibit purified PfENR enzyme with IC 50 values of <200 nM. This study has significantly expanded the knowledge base with regard to the structure-activity relationship of triclosan while affording gains against cultured parasites and purified PfENR enzyme. In contrast to a recent report in the literature, these results demonstrate the ability to improve the in vitro potency of triclosan significantly by replacing the suboptimal 5-chloro group with larger hydrophobic moieties. The biological and x-ray crystallographic data thus demonstrate the flexibility of the active site and point to future rounds of optimization to improve compound potency against purified enzyme and intracellular Plasmodium parasites.

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“…Our study also revealed the structural basis for the enhanced affinity of triclosan in the presence of a cofactor and the better binding of the cofactor in the ternary complex (20). Different triclosan analogues were generated and tested against different organisms such as E. coli ENR (EcENR) (28) and M. tuberculosis InhA (MtENR) (29,30). Freundlich et al have also synthesized and tested 2 0 , 4 0 , and 4 substituted triclosan derivatives for their biological activity against PfENR (31)(32)(33).…”

Section: Introductionmentioning

confidence: 93%

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

Maity¹,

Bhargav²,

Sankaran³

et al. 2010

IUBMB Life

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SummaryTriclosan, a well-known inhibitor of Enoyl Acyl Carrier Protein Reductase (ENR) from several pathogenic organisms, is a promising lead compound to design effective drugs. We have solved the X-ray crystal structures of Plasmodium falciparum ENR in complex with triclosan variants having different substituted and unsubstituted groups at different key functional locations. The structures revealed that 4 and 2 0 substituted compounds have more interactions with the protein, cofactor, and solvents when compared with triclosan. New water molecules were found to interact with some of these inhibitors. Substitution at the 2 0 position of triclosan caused the relocation of a conserved water molecule, leading to an additional hydrogen bond with the inhibitor. This observation can help in conserved water-based inhibitor design. 2 0 and 4 0 unsubstituted compounds showed a movement away from the hydrophobic pocket to compensate for the interactions made by the halogen groups of triclosan. This compound also makes additional interactions with the protein and cofactor which compensate for the lost interactions due to the unsubstitution at 2 0 and 4 0 . In cell culture, this inhibitor shows less potency, which indicates that the chlorines at 2 0 and 4 0 positions increase the ability of the inhibitor to cross multilayered membranes. This knowledge helps us to modify the different functional groups of triclosan to get more potent inhibitors. IUBMBIUBMB Life, 62(6): [467][468][469][470][471][472][473][474][475][476] 2010

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High Affinity InhA Inhibitors with Activity against Drug-Resistant Strains of Mycobacterium tuberculosis

Cited by 235 publications

References 52 publications

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

Novel Inhibitors of InhA Efficiently Kill Mycobacterium tuberculosis under Aerobic and Anaerobic Conditions

X-ray Structural Analysis of Plasmodium falciparum Enoyl Acyl Carrier Protein Reductase as a Pathway toward the Optimization of Triclosan Antimalarial Efficacy

X‐ray crystallographic analysis of the complexes of enoyl acyl carrier protein reductase of Plasmodium falciparum with triclosan variants to elucidate the importance of different functional groups in enzyme inhibition

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