Inhibition of M. tuberculosis β-ketoacyl CoA reductase FabG4 (Rv0242c) by triazole linked polyphenol–aminobenzene hybrids: Comparison with the corresponding gallate counterparts

Banerjee, Deb Ranjan; Senapati, Kalyan; Biswas, Rupam; Das, Amit Kumar; Basak, Amit

doi:10.1016/j.bmcl.2015.01.014

Cited by 6 publications

(6 citation statements)

References 18 publications

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“…Recent advances in the development of inhibitors against Mt FabG4 are reviewed comprehensively by Dutta 18 . Successful inhibitors targeting Mt FabG4 NADH binding sites include triazole linked polyphenol or polyphenol-aminobenzene hybrids 7 , 8 . Dual inhibitors of Mt FabG4 and HtdX, another enzyme that belongs to the same operon in M. tuberculosis and is presumed to play a role in fatty acid metabolism, bind at catalytic loops 7 , 8 .…”

Section: Resultsmentioning

confidence: 99%

“…Successful inhibitors targeting Mt FabG4 NADH binding sites include triazole linked polyphenol or polyphenol-aminobenzene hybrids 7 , 8 . Dual inhibitors of Mt FabG4 and HtdX, another enzyme that belongs to the same operon in M. tuberculosis and is presumed to play a role in fatty acid metabolism, bind at catalytic loops 7 , 8 . A specifically designed synthetic inhibitor of Mt FabG4, S-S006-830, found two putative binding regions; the first near the substrate/coenzyme binding sites in the C-terminal domain and the other at a smaller pocket on the N-terminal domain 58 .…”

Section: Resultsmentioning

confidence: 99%

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Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

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Adams

Waters

et al. 2021

Sci Rep

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Treatments for ‘superbug’ infections are the focus for innovative research, as drug resistance threatens human health and medical practices globally. In particular, Acinetobacter baumannii (Ab) infections are repeatedly reported as difficult to treat due to increasing antibiotic resistance. Therefore, there is increasing need to identify novel targets in the development of different antimicrobials. Of particular interest is fatty acid synthesis, vital for the formation of phospholipids, lipopolysaccharides/lipooligosaccharides, and lipoproteins of Gram-negative envelopes. The bacterial type II fatty acid synthesis (FASII) pathway is an attractive target for the development of inhibitors and is particularly favourable due to the differences from mammalian type I fatty acid synthesis. Discrete enzymes in this pathway include two reductase enzymes: 3-oxoacyl-acyl carrier protein (ACP) reductase (FabG) and enoyl-ACP reductase (FabI). Here, we investigate annotated FabG homologs, finding a low-molecular weight 3-oxoacyl-ACP reductase, as the most likely FASII FabG candidate, and high-molecular weight 3-oxoacyl-ACP reductase (HMwFabG), showing differences in structure and coenzyme preference. To date, this is the second bacterial high-molecular weight FabG structurally characterized, following FabG4 from Mycobacterium. We show that ΔAbHMwfabG is impaired for growth in nutrient rich media and pellicle formation. We also modelled a third 3-oxoacyl-ACP reductase, which we annotated as AbSDR. Despite containing residues for catalysis and the ACP coordinating motif, biochemical analyses showed limited activity against an acetoacetyl-CoA substrate in vitro. Inhibitors designed to target FabG proteins and thus prevent fatty acid synthesis may provide a platform for use against multidrug-resistant pathogens including A. baumannii.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

Cross

Adams

Waters

et al. 2021

Sci Rep

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“…1,3-Bis(2,6-dimethylphenyl)thiourea (L) [L = (ArNH) 2 C = S; Ar = 2,6-Me 2 C 6 H 3 ] was synthesized according to a literature procedure. 16 Benzyl azide, 22c 3-chlorobenzyl azide 29 and 4-nitrobenzyl azide 30 were prepared according to literature procedures. All alkynes were used directly as received.…”

Section: Generalmentioning

confidence: 99%

An efficient and recyclable thiourea-supported copper(i) chloride catalyst for azide–alkyne cycloaddition reactions

2016

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“…The FAS-II enzyme FabG4 has been shown to be conserved among pathogenic Mycobacterium species [3]. It has been identified as a putative drug target for triazole-linked polyphenol-gallol and polyphenolaminobenzene hybrids, which may be used as alternate antitubercular drugs [17,18] underscoring the prospect of FabG4 as a druggable target in other pathogenic mycobacteria. Hence, the study was undertaken to unearth the potential role of the FAS-II gene MFfabG4 in the pathophysiology of M. fortuitum.…”

Section: Mffabg4 Imparts Nutrient Starvation Stress Tolerance To M Fo...mentioning

confidence: 99%

Mycobacterium fortuitum fabG4knockdown studies: Implication as pellicle and biofilm specific drug target

2022

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The fatty acid biosynthesis pathway is crucial for the formation of the mycobacterial cell envelope. The fatty acid synthase type-II (FAS-II) components are attractive targets for designing anti-biofilm inhibitors.Literature review, bioinformatics analysis, cloning, and sequencing led to the identification of a novel Mycobacterium fortuitum FAS-II gene MFfabG4 which interacts with mycobacterial proteins involved in biofilm formation. A manually curated M. fortuitum fatty acid biosynthesis pathway has been proposed exploiting functional studies from the Kyoto Encyclopedia of Genes and Genomes and Mycobrowser databases for MFFabG4. M. fortuitum MFfabG4 knockdown strain (FA) was constructed and validated by quantitative polymerase chain reaction. The FA strain displayed unstructured smooth colony architecture, correlating with decreased pathogenicity and virulence. MFfabG4 knockdown resulted in diminished pellicle and attenuated biofilm formation, along with impaired sliding motility, and reduced cell sedimentation. The FA strain showed lowered cell surface hydrophobicity, indicating attenuation in M. fortuitum intracellular infection-causing ability. Stress survival studies showed the requirement of MFfabG4 for survival in a nutrient-starved environment. The results indicate that MFfabG4 maintains the physiology of the cell envelope and is required for the formation of M. fortuitum pellicle and biofilm. The study corroborates the role of MFfabG4 as a pellicle-and biofilm-specific drug target and a potential diagnostic marker for M. fortuitum and related pathogenic mycobacteria.

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Inhibition of M. tuberculosis β-ketoacyl CoA reductase FabG4 (Rv0242c) by triazole linked polyphenol–aminobenzene hybrids: Comparison with the corresponding gallate counterparts

Cited by 6 publications

References 18 publications

Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

Insights into Acinetobacter baumannii fatty acid synthesis 3-oxoacyl-ACP reductases

An efficient and recyclable thiourea-supported copper(i) chloride catalyst for azide–alkyne cycloaddition reactions

Mycobacterium fortuitum fabG4knockdown studies: Implication as pellicle and biofilm specific drug target

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