Antibacterial FabH Inhibitors with Mode of Action Validated in <i>Haemophilus influenzae</i> by in Vitro Resistance Mutation Mapping

McKinney, David C.; Eyermann, Charles J.; Gu, Rong-Fang; Hu, Jun; Kazmirski, Steven L.; Lahiri, S. C.; McKenzie, Andrew R.; Shapiro, Adam B.; Breault, Gloria A.

doi:10.1021/acsinfecdis.6b00053

Cited by 53 publications

(46 citation statements)

References 23 publications

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“…BioZ is a FabH (β-ketoacyl-ACP synthase) homologue and not an α/β-hydrolase. It has a catalytic Cys/His/Asn triad 47 , 48 . Thus, it is not able to cleave the methyl ester like BioH with its catalytic Ser.…”

Section: Resultsmentioning

confidence: 99%

The Thaumarchaeon N. gargensis carries functional bioABD genes and has a promiscuous E. coli ΔbioH-complementing esterase EstN1

Chow

Danso

Ferrer

et al. 2018

Sci Rep

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Biotin is an essential cofactor required for carboxylation and decarboxylation reactions in all domains of life. While biotin biosynthesis in most Bacteria and Eukarya is well studied, the complete pathway for this vitamer in Archaea is still not known. Detailed genome searches indicated the presence of possible bio gene clusters only in Methanococcales and Thaumarchaeota. Therefore, we analysed the functionality of the predicted genes bioA, bioB, bioD and bioF in the Thaumarchaeon Nitrososphaera gargensis Ga2.9 which are essential for the later steps of biotin synthesis. In complementation tests, the gene cluster-encoded N. gargensis bioABD genes except bioF restored growth of corresponding E. coli Rosetta-gami 2 (DE3) deletion mutants. To find out how biotin biosynthesis is initiated, we searched the genome for a possible bioH analogue encoding a pimeloyl-ACP-methylester carboxylesterase. The respective amino acid sequence of the ORF estN1 showed weak conserved domain similarity to this class of enzymes (e-value 3.70e−42). Remarkably, EstN1 is a promiscuous carboxylesterase that complements E. coli ΔbioH and Mesorhizobium loti ΔbioZ mutants for growth on biotin-free minimal medium. Additional 3D-structural models support the hypothesis that EstN1 is a BioH analogue. Thus, this is the first report providing experimental evidence that Archaea carry functional bio genes.

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Section: Resultsmentioning

confidence: 99%

The Thaumarchaeon N. gargensis carries functional bioABD genes and has a promiscuous E. coli ΔbioH-complementing esterase EstN1

Chow

Danso

Ferrer

et al. 2018

Sci Rep

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“…High quality crystallographic structures of target proteins of E.coli and S. aureus with good resolution were retrieved from Protein data bank (Fig. 2) [52] were selected to understand molecular interactions between nanoparticles and active pocket residues of protein.…”

Section: Molecular Docking Studymentioning

confidence: 99%

Comparative Study of Selenides and Tellurides of Transition Metals (Nb and Ta) with Respect to its Catalytic, Antimicrobial, and Molecular Docking Performance

et al. 2020

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The present research is a comparative study that reports an economical and accessible method to synthesize niobium (Nb) and Tantalum (Ta) selenides and tellurides with useful application in the removal of pollutants in textile, paper, and dyeing industries as well as in medical field. In this study, solid-state process was used to generate nanocomposites and various characterization techniques were employed to compare two groups of materials under investigation. Structure, morphology, elemental constitution, and functional groups of synthesized materials were analyzed with XRD, FESEM coupled with EDS, FTIR, and Raman spectroscopy, respectively. HR-TEM images displayed nanoscale particles with tetragonal and monoclinic crystal structures. The optical properties were evaluated in terms of cutoff wavelength and optical band gap using UV-visible spectroscopy. A comparative behavior of both groups of compounds was assessed with regards to their catalytic and microcidal properties. Extracted nanocomposites when used as catalysts, though isomorphs of each other, showed markedly different behavior in catalytic degradation of MB dye in the presence of NaBH 4 that was employed as a reducing agent. This peculiar deviation might be attributed to slight structural differences between them. Escherichia coli and Staphylococcus aureus (G-ve and + ve bacteria, respectively) were designated as model strains for in vitro antibacterial tests of both clusters by employing disk diffusion method. Superior antibacterial efficacy was observed for telluride system (significant inhibition zones of 26-35 mm) compared with selenide system (diameter of inhibition zone ranged from 0.8 mm to 1.9 mm). In addition, molecular docking study was undertaken to ascertain the binding interaction pattern between NPs and active sites in targeted cell protein. The findings were in agreement with antimicrobial test results suggesting NbTe 4 to be the best inhibitor against FabH and FabI enzymes.

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“…The two best characterized molecular targets are FabI and FabH, which have been subject to numerous discovery campaigns by a variety of investigators. One major recurring result from these campaigns is the difficulty in getting both spectrum and potency [9,21,99,104-107,123]. For example, a recent FabH discovery campaign reported a series of 22 thiolactomycin analogues and tested these analogues against Mycobacterium tuberculosis , Francisella tularensis , Yersinia pestis , and Staphylococcus aureus [99].…”

Section: Antibiotic Discovery In Bacterial Fatty Acid Metabolismmentioning

confidence: 99%

Bacterial fatty acid metabolism in modern antibiotic discovery

Yao

Rock

2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Bacterial fatty acid synthesis is essential for many pathogens and different from the mammalian counterpart. These features make bacterial fatty acid synthesis a desirable target for antibiotic discovery. The structural divergence of the conserved enzymes and the presence of different isozymes catalyzing the same reactions in the pathway make bacterial fatty acid synthesis a narrow spectrum target rather than the traditional broad spectrum target. Furthermore, bacterial fatty acid synthesis inhibitors are single-targeting, rather than multi-targeting like traditional monotherapeutic, broad-spectrum antibiotics. The single-targeting nature of bacterial fatty acid synthesis inhibitors makes overcoming fast-developing, target-based resistance a necessary consideration for antibiotic development. Target-based resistance can be overcome through multi-targeting inhibitors, a cocktail of single-targeting inhibitors, or by making the single targeting inhibitor sufficiently high affinity through a pathogen selective approach such that target-based mutants are still susceptible to therapeutic concentrations of drug. Many of the pathogens requiring new antibiotic treatment options encode for essential bacterial fatty acid synthesis enzymes. This review will evaluate the most promising targets in bacterial fatty acid metabolism for antibiotic therapeutics development and review the potential and challenges in advancing each of these targets to the clinic and circumventing target-based resistance.

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Antibacterial FabH Inhibitors with Mode of Action Validated in Haemophilus influenzae by in Vitro Resistance Mutation Mapping

Cited by 53 publications

References 23 publications

The Thaumarchaeon N. gargensis carries functional bioABD genes and has a promiscuous E. coli ΔbioH-complementing esterase EstN1

The Thaumarchaeon N. gargensis carries functional bioABD genes and has a promiscuous E. coli ΔbioH-complementing esterase EstN1

Comparative Study of Selenides and Tellurides of Transition Metals (Nb and Ta) with Respect to its Catalytic, Antimicrobial, and Molecular Docking Performance

Bacterial fatty acid metabolism in modern antibiotic discovery

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