A FabG inhibitor targeting an allosteric binding site inhibits several orthologs from Gram-negative ESKAPE pathogens

Vella, Peter; Rudraraju, Reshma Srilakshmi; Lundbäck, Thomas; Axelsson, Hanna; Almqvist, Helena; Vallin, Michaela; Schneider, Günter; Schnell, R.

doi:10.1016/j.bmc.2020.115898

Cited by 16 publications

(13 citation statements)

References 35 publications

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“…2). These structures are PDB entry 1iy8, the crystal structure of levodione reductase from Leifsonia aquatica (Sogabe et al, 2003), PDB entry 3ftp, a 3-ketoacyl-(acyl-carrier-protein) reductase from Burkholderia pseudomallei (Baugh et al, 2013), PDB entry 6t6n, Klebsiella pneumoniae FabG2(NADH-dependent) in complex with NADH (Vella et al, 2021), and PDB entry 6ixm, ketone reductase ChKRED20 from the genome of Chryseobacterium (Li et al, 2019). Interestingly, while all of the other structures have well conserved cofactor-binding domains, an extended loop connecting the first strand in the N-terminus to Figure 1…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of a putative short-chain dehydrogenase/reductase from Paraburkholderia xenovorans

Davidson¹,

Nicholas²,

Young³

et al. 2022

Acta Cryst Sect F

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Paraburkholderia xenovorans degrades organic wastes, including polychlorinated biphenyls. The atomic structure of a putative dehydrogenase/reductase (SDR) from P. xenovorans (PxSDR) was determined in space group P21 at a resolution of 1.45 Å. PxSDR shares less than 37% sequence identity with any known structure and assembles as a prototypical SDR tetramer. As expected, there is some conformational flexibility and difference in the substrate-binding cavity, which explains the substrate specificity. Uniquely, the cofactor-binding cavity of PxSDR is not well conserved and differs from those of other SDRs. PxSDR has an additional seven amino acids that form an additional unique loop within the cofactor-binding cavity. Further studies are required to determine how these differences affect the enzymatic functions of the SDR.

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Section: Resultsmentioning

confidence: 99%

Crystal structure of a putative short-chain dehydrogenase/reductase from Paraburkholderia xenovorans

Davidson¹,

Nicholas²,

Young³

et al. 2022

Acta Cryst Sect F

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“…FabI is the target of the antimicrobial drugs triclosan and isoniazid, as well as the clinical trial-stage compounds afabicin ( 66 , 67 ), CG400549 ( 68 ), and MUT056399 ( 69 ). Inhibitors of FabG have also been described ( 70 – 73 ), but the presence of multiple isoforms of FabG in some organisms may make it an unsuitable target ( 71 ). Each protein also has several human homologs, making these targets potentially difficult for multitarget inhibitor development.…”

Section: Resultsmentioning

confidence: 99%

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

Hardy¹

2022

Microbiol Spectr

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“…Several crystal structures of FabG are available in the PDB from E. coli (PDB ID 1I01) [ 41 ], A. baumannii (PDB ID 6T65) [ 98 ], and P. aeruginosa (PDB ID 4AG3) [ 94 ], for example. In solution, its active quaternary structure is homotetramer ( Figure 17 A).…”

Section: Fas-ii Enzymes and Their Corresponding Inhibitorsmentioning

confidence: 99%

“…In 2021, Vella et al highlighted two hits, CBK261309C and CBK066822 ( Figure 19 ), via small-molecule screening as potential FabG inhibitors [ 98 ]. The activity of FabG in the presence of thirty-three thousand compounds was assessed by following the formation of NADP + .…”

Section: Fas-ii Enzymes and Their Corresponding Inhibitorsmentioning

confidence: 99%

A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs

et al. 2023

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Resistance to antimicrobial drugs is currently a serious threat to human health. Consequently, we are facing an urgent need for new antimicrobial drugs acting with original modes of action. The ubiquitous and widely conserved microbial fatty acid biosynthesis pathway, called FAS‑II system, represents a potential target to tackle antimicrobial resistance. This pathway has been extensively studied, and eleven proteins have been described. FabI (or InhA, its homologue in mycobacteria) was considered as a prime target by many teams and is currently the only enzyme with commercial inhibitor drugs: triclosan and isoniazid. Furthermore, afabicin and CG400549, two promising compounds which also target FabI, are in clinical assays to treat Staphylococcus aureus. However, most of the other enzymes are still underexploited targets. This review, after presenting the FAS-II system and its enzymes in Escherichia coli, highlights the reported inhibitors of the system. Their biological activities, main interactions formed with their targets and structure–activity relationships are presented as far as possible.

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A FabG inhibitor targeting an allosteric binding site inhibits several orthologs from Gram-negative ESKAPE pathogens

Cited by 16 publications

References 35 publications

Crystal structure of a putative short-chain dehydrogenase/reductase from Paraburkholderia xenovorans

Crystal structure of a putative short-chain dehydrogenase/reductase from Paraburkholderia xenovorans

Essential Paralogous Proteins as Potential Antibiotic Multitargets in Escherichia coli

A Review of Fatty Acid Biosynthesis Enzyme Inhibitors as Promising Antimicrobial Drugs

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