AG205, a Novel Agent Directed against FabK of
            <i>Streptococcus pneumoniae</i>

Takahata, Sho; Iida, M.; Osaki, Yumi; Saito, Jun; Kitagawa, Hideo; Ozawa, Tomohiro; Yoshida, Takuji; Hoshiko, Shigeru

doi:10.1128/aac.00270-06

Cited by 22 publications

(19 citation statements)

References 14 publications

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“…The enzymatic reaction proceeds via a Bi-Bi double displacement (or Ping-Pong) mechanism, with the NADH cofactor binding first to the active site and reducing the FMN group, followed by displacement of NAD + by the enoyl substrate, which is reduced by the FMNH 2 group, thereby returning the enzyme to its original state [18]. Inhibitor screening studies that have been performed against the SpFabK enzyme used concentrations for crotonyl-CoA and NADH significantly greater than the reported K m values (200 µM and 400 µM, respectively) [24]. The use of balanced assay conditions, where the assay concentrations of cofactor and substrate are near their K m values, maximizes the chances of finding inhibitors with the broadest diversity in terms of mechanism of inhibition (competitive, noncompetitive, uncompetitive) [25].…”

Section: Resultsmentioning

confidence: 99%

Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis

Hevener

Mehboob

Boci

et al. 2012

Protein Expression and Purification

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Section: Resultsmentioning

confidence: 99%

Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis

Hevener

Mehboob

Boci

et al. 2012

Protein Expression and Purification

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“…Although novel FabI inhibitors targeting S. aureus have been reported by several groups (Heerding et al 2001; Seefeld et al 2001; Ling et al 2004; Kitagawa et al 2007a; Takahata et al 2007; Yum et al 2007), there are only a few reports of FabK inhibitors (Payne et al 2002; Seefeld et al 2003; Zheng et al 2006). We have reported the inhibitor AG205 and more effective FabK inhibitors showing both FabK inhibitory activity and antibacterial activity against S. pneumoniae (Takahata et al 2006; Kitagawa et al 2007b,c). Inhibitors designed to target FabK are attractive as antibiotics against microorganisms that utilize the FabK pathway, in particular, S. pneumoniae .…”

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confidence: 99%

Crystal structure of enoyl–acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor

et al. 2008

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Enoyl-acyl carrier protein (ACP) reductases are critical for bacterial type II fatty acid biosynthesis and thus are attractive targets for developing novel antibiotics. We determined the crystal structure of enoyl-ACP reductase (FabK) from Streptococcus pneumoniae at 1.7 Å resolution. There was one dimer per asymmetric unit. Each subunit formed a triose phosphate isomerase (TIM) barrel structure, and flavin mononucleotide (FMN) was bound as a cofactor in the active site. The overall structure was similar to the enoyl-ACP reductase (ER) of fungal fatty acid synthase and to 2-nitropropane dioxygenase (2-ND) from Pseudomonas aeruginosa, although there were some differences among these structures. We determined the crystal structure of FabK in complex with a phenylimidazole derivative inhibitor to envision the binding site interactions. The crystal structure reveals that the inhibitor binds to a hydrophobic pocket in the active site of FabK, and this is accompanied by induced-fit movements of two loop regions. The thiazole ring and part of the ureido moiety of the inhibitor are involved in a face-to-face p-p stacking interaction with the isoalloxazine ring of FMN. The side-chain conformation of the proposed catalytic residue, His144, changes upon complex formation. Lineweaver-Burk plots indicate that the inhibitor binds competitively with respect to NADH, and uncompetitively with respect to crotonoyl coenzyme A. We propose that the primary basis of the inhibitory activity is competition with NADH for binding to FabK, which is the first step of the two-step ping-pong catalytic mechanism.Keywords: FabK; enoyl-acyl carrier protein reductase; fatty acid biosynthesis; antibiotics; inhibitor Streptococcus pneumoniae causes community-acquired infections such as pneumonia, otitis media, and meningitis. The increase of penicillin-and/or macrolide-resistant S. pneumoniae is of great concern worldwide, and, moreover, the emergence of quinolone-resistant S. pneumoniae has been reported recently (Cohen 1992;Bartlett et al. 1998;Johnson et al. 2005). A key strategy to overcoming antibiotic resistance is the discovery of antibacterial agents with novel mechanisms of action that have no crossresistance.The bacterial type II fatty acid synthase complex comprises discrete enzyme activities encoded by discrete genes, in contrast to the multifunctional type I fatty acid synthase in mammals (Rock and Cronan 1996). These bacterial enzymes are attractive targets for the development of novel selective antibacterial agents (Heath et al. 2001). Enoyl-acyl carrier protein (ACP) reductase is Reprint requests to: Jun Saito, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, Japan; e-mail: jun_saito@meiji.co.jp; fax: 81-45-545-3152.Abbreviations: ACP, acyl carrier protein; FAD, flavin adenine dinucleotide; FAS II, bacterial type II fatty acid biosynthesis; FMN, flavin mononucleotide; MAD, multiple-wavelength anomalous dispersion; NADH, nicotinamide adenine dinucleotide; ER, enoyl-ACP ...

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“…Although an alternative enoyl-ACP reductase, FabK, which displays no significant sequence homology to FabI, was identified in Streptococcus pneumoniae, Enterococcus faecalis and Pseudomonas aeruginosa [8], genomic studies have revealed that most bacteria possess FabI as the sole enoyl-ACP reductase. There are several recent reports of FabI inhibitors with antibacterial activity against S. aureus [9ϳ11], or a novel FabK inhibitor with antipneumococcal activity [12].…”

Section: Introductionmentioning

confidence: 99%

Discovery of 4-Pyridone Derivatives as Specific Inhibitors of Enoyl-Acyl Carrier Protein Reductase (FabI) with Antibacterial Activity against Staphylococcus aureus

et al. 2007

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4-Pyridone derivatives were identified as potent inhibitors of FabI, the enoyl-acyl carrier protein reductase in Escherichia coli and Staphylococcus aureus. 1-Substituted derivatives of a hit compound exhibited potent antibacterial activities against S. aureus. Target specificity of 4-pyridone derivatives was confirmed by the strong inhibition of lipid synthesis in macromolecular biosynthesis assay and also by the reduced antimicrobial activity against triclosan-resistant S. aureus isolates possessing a point mutation (Ala95Val) in FabI. Two 4-pyridone compounds exhibited strong antibacterial activities against 30 clinical isolates of methicillin-resistant S. aureus (MRSA) with MIC 90 of 0.5 and 2 m g/ml, respectively. Moreover, they retained activity against S. aureus with a mutation affecting FabI residue 204, which was recently found to be associated with triclosan resistance in clinical isolates of S. aureus. In conclusion, we have identified a novel chemical series, 4-pyridone derivatives, as specific inhibitors of FabI with potent antibacterial activity against S. aureus.

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AG205, a Novel Agent Directed against FabK of Streptococcus pneumoniae

Cited by 22 publications

References 14 publications

Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis

Expression, purification and characterization of enoyl-ACP reductase II, FabK, from Porphyromonas gingivalis

Crystal structure of enoyl–acyl carrier protein reductase (FabK) from Streptococcus pneumoniae reveals the binding mode of an inhibitor

Discovery of 4-Pyridone Derivatives as Specific Inhibitors of Enoyl-Acyl Carrier Protein Reductase (FabI) with Antibacterial Activity against Staphylococcus aureus

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