Inhibitors of glucosamine-6-phosphate synthase as potential antimicrobials or antidiabetics - synthesis and properties.
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ABSTRACT:
SUBMITTER: Stefaniak J
PROVIDER: S-EPMC9272926 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundPreservatives have to be added in food, pharmaceuticals and cosmetics products to maintain their shelf life. However, the existing chemical based preservatives have been associated with severe side effects that compel the researchers to find better safe preservatives based on natural products. G-6-P synthase is an important enzyme for bacterial and fungal cell wall synthesis and offers as a potential target to find better G-6-P synthase inhibitors based antimicrobial compounds. Naringenin, a flavanone, has been reported for a wide range of pharmacological activities including antimicrobial activity, which makes it a potential candidate to be explored as novel G-6-P synthase inhibitor.ResultsThe synthesis of naringenin derivatives with potent G-6-P synthase inhibitor having remarkable antioxidant, antimicrobial and preservative efficacy was performed. Among the synthesized compounds, the compound 1 possessed good antioxidant activity (IC50 value, 6.864 ± 0.020 µM) as compared to standard ascorbic acid (IC50 value, 8.110 ± 0.069 µM). The antimicrobial activity of synthesized compounds revealed compound 1 as the most potent compound (pMIC 1.79, 1.79, 1.49, 1.49, 1.49 and 1.49 μM/mL for P. mirabilis, P. aeruginosa, S. aureus, E. coli, C. albicans and A. niger respectively) as compared to standard drugs taken. The compound 2 showed comparable activity against P. mirabilis (pMIC 1.14 μM/mL), C. albicans (pMIC 1.14 μM/mL) while the compound 3 also showed comparable activity against C. albicans (pMIC 1.16 μM/mL) as well A. niger (pMIC 1.46 μM/mL), likewise the compound 4 showed comparable activity against P. mirabilis (pMIC 1.18 μM/mL) as compared to the standard drugs streptomycin (pMIC 1.06, 1.36, 1.06 and 1.96 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ciprofloxacin (pMIC 1.12, 1.42, 1.12 and 1.42 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively), ampicillin (pMIC 1.14, 0.84, 0.84 and 1.74 μM/mL for P. mirabilis, P. aeruginosa, S. aureus and E. coli respectively) and fluconazole (pMIC 1.08 and 1.38 μM/mL for C. albicans and A. niger respectively). The molecular docking with the target G-6-P synthase pdb id 1moq resulted with an better dock score for compound 1 (- 7.42) as compared to standard antimicrobial drugs, ciprofloxacin (- 5.185), ampicillin (- 5.065) and fluconazole (- 5.129) that supported the wet lab results. The preservative efficacy test for compound 1 in White Lotion USP showed the log CFU/mL value within the prescribed limit and results were comparable to standard sodium benzoate, ethyl paraben and propyl paraben as per USP standard protocol.ConclusionsThe synthesized naringenin derivatives exhibited significant G-6-P synthase inhibitory potential with good selectivity towards the selected target G-6-P synthase. Compound 1, bearing nitro group showed good antioxidant, antimicrobial and preservative efficacy compared with the standard drugs taken. The mechanistic insight about the compounds within the active site was completed by molecular docking that supported the results for novel synthesized G-6-P synthase inhibitors.
| S-EPMC7305605 | biostudies-literature
Project description:Glucosamine-6-Phosphate synthase enzyme has been targeted for development of better and safe preservative due to its role in microbial cell wall synthesis. In recent year's demand of preservatives for the food, cosmetics and pharmaceuticals have increased. Although, the available synthetic preservatives have associated unwanted adverse effects, soa chain of naringin derivatives were schemed synthesized and judged for antioxidant, antimicrobial, preservative efficacy, stability study and topical evaluation. Molecular docking resulted with excellent dock score and binding energy for compound 7, compound 6 and compound 1 as compared to standard drugs. Resultant data of antimicrobial activity revealed compound 7as most potent antimicrobial compound for P. mirabilis, P. aeruginosa, S. aureus, E. coli, C. albicans, and A. niger, respectively, as compared to the standard drugs. The preservative efficacy test of compound 7 in White Lotion USP showed the log cfu/mL value within prescribed limit of USP standard. Compound 7 stabilize the White lotion USP from microbial growth for a period of six months under accelerated storage condition. Compound 7 was further evaluated for toxicity by using the Draize test in rabbits and showed no sign of eye and skin irritation. The outcome demonstrated that synthesized naringin compounds showed glorious antioxidant, antimicrobial, preservative efficacy, stable and safe as compared to standards.
| S-EPMC7686335 | biostudies-literature
Project description:Recent expansion of immunocompromised population has led to significant rise in zygomycosis caused by filamentous fungus Rhizopus oryzae. Due to emergence of fungal resistance and side-effects of antifungal drugs, there is increased demand for novel drug targets. The current study elucidates molecular interactions of peptide drugs with G-6-P synthase (catalyzing the rate-limiting step of fungal cell wall biosynthetic pathway) of R.oryzae by molecular docking studies. The PDB structures of enzyme in R.oryzae are not known which were predicted using I-TASSER server and validated with PROCHECK. Peptide inhibitors, FMDP and ADGP previously used against enzyme of E.coli (PDBid: 1XFF), were used for docking studies of enzyme in R.oryzae by SchrödingerMaestro v9.1. To investigate binding between enzyme and inhibitors, Glide and Induced Fit docking were performed. IFD results of 1XFF with FMDP yielded C1, R73, W74, T76, G99 and D123 as the binding sites. C379 and Q427 appear to be vital for binding of R.oryzae enzymes to inhibitors. The comparison results of IFD scores of enzyme in R.oryzae and E.coli (PDBid: 2BPL) yield appreciable score, hinting at the probable effectiveness of inhibitors FMDP and ADGP against R.oryzae, with ADGP showing an improved enzyme affinity. Moreover, the two copies of gene G-6-P synthase due to extensive fungal gene duplication, in R. oryzae eliminating the problem of drug ineffectiveness could act as a potential antifungal drug target in R. oryzae with the application of peptide ligands.
| S-EPMC3280496 | biostudies-literature
Project description:Functional and structural properties of several truncated or mutated variants of Candida albicans Gfa1p (glucosamine-6-phosphate synthase) were compared with those of the wild-type enzyme. Fragments encompassing residues 1-345 and 346-712 of Gfa1p, expressed heterogeneously in bacterial host as His6 fusions, were identified as the functional GAH (glutamine amidehydrolysing) and ISOM (hexose phosphate-isomerizing) domains respectively. It was found that the native GAH domain is monomeric, whereas the native ISOM domain forms tetramers, as does the whole enzyme. Spectrofluorimetric and kinetic studies of the isolated domains, the Delta218-283Gfa1p mutein and the wild-type enzyme revealed that the binding site for the feedback inhibitor, uridine 5'-diphospho-N-acetyl-D-glucosamine, is located in the ISOM domain. Inhibitor binding affects amidohydrolysing activity of the GAH domain and, as a consequence, the GlcN-6-P (D-glucosamine-6-phosphate)-synthetic activity of the whole enzyme. The fragment containing residues 218-283 is neither involved in ligand binding nor in protein oligomerization. Comparison of the catalytic activities of Gfa1p(V711F), Delta709-712Gfa1p, Gfa1p(W97F) and Gfa1p(W97G) with those of the native Gfa1p and the isolated domains provided evidence for an intramolecular channel connecting the GAH and ISOM domains of Gfa1p. The channel becomes leaky upon deletion of amino acids 709-712 and in the W97F and W97G mutants. The Trp97 residue was found to function as a molecular gate, opening and closing the channel. The W97G and V711F mutations resulted in an almost complete elimination of the GlcN-6-P-synthetic activity, with the retention of the amidohydrolase and sugar phosphate-isomerizing activities.
| S-EPMC1868842 | biostudies-literature
Project description:The dapdiamides make up a family of antibiotics that have been presumed to be cleaved in the target cell to enzyme-inhibitory N-acyl-2,3-diaminopropionate (DAP) warheads containing two alternative electrophilic moieties. Our prior biosynthetic studies revealed that an eneamide warhead is made first and converted to an epoxyamide via a three-enzyme branch pathway. Here we provide a rationale for this logic. We report that the R,R-epoxyamide warhead is a more efficient covalent inactivator of glucosamine-6-phosphate synthase by 1 order of magnitude versus the eneamide, and this difference correlates with a >10-fold difference in antibiotic activity for the corresponding acyl-DAP dipeptides.
| S-EPMC3097904 | biostudies-literature
Project description:Invasive fungal opportunistic infections or mycoses have been on the rise with increase in the number of immuno-compromised patients accounting for associated high morbidity and mortality rates. The antifungal drugs are not completely effective due to increased resistance and varied susceptibility of fungi. Hence, the functional diversification study of novel targets has to be carried out. The enzyme glucosamine-6-phosphate synthase [EC 2.6.1.16], a novel drug target, catalyzes the rate-limiting step of the fungal cell-wall biosynthetic pathway, comprising four conserved domains, two glutaminase and sugar-isomerising (SIS) domains with active site. The amino acids within these domains tend to mutate simultaneously and exert mutual selective forces which might result in untoward fungal adaptations that are fixed through random genetic drift over time. The current study is an attempt to investigate such 'non-independent' coevolving residues which play critical functional and structural role in the protein. Residues with Shannon entropy ≦1 (calculated by the Protein Variability Server) were considered and subsequently, positional correlations were estimated by InterMap3D 1.3 server. It was observed that majority of coevolving pairs of first SIS domain involved interactions with hydrophobic leucine and found to be spatially coupled in 3-dimensional structure of the enzyme. The coevolving groups of Aspergillus niger and Rhizopus oryzae species might play a role in drug resistance. Such coevolutionary analysis is important for understanding the receptor-ligand interactions and effective drug designing.
| S-EPMC3163925 | biostudies-literature
Project description:The immunosuppressive individuals are highly prone to get afflicted with invasive opportunistic fungal infections such as Candidiasis, Aspergillosis, Histoplasmosis, Coccidioidomycosis, Blastomycosis, Penicilliosis, Cryptococcosis and Zygomycosis which are becoming a cause of concern to the mankind due to their high morbidity and mortality rates. The existing antifungal agents are not completely effective due to their severe side-effects and recurrent drug resistance in fungi. Hence, there is an urgent need to develop newer and better antifungal drugs. The enzyme Glucosamine-6-phosphate (G-6-P) synthase catalyzes the ratelimiting step of the fungal cell-wall biosynthetic pathway and targeting it can inhibit the growth of the fungus. The present study attempts to investigate the inherent variations in functional domain viz. Glutaminase (GATase II) and Sugar Isomerising (SIS) of Glucosamine-6-phosphate (G-6-P) synthase enzyme of mycoses-causing fungi. These domains may be identified as probable active site(s). Multiple sequence alignment performed using ClustalX2 and construction of phylogenetic tree of individual domains by MEGA v5.0 helped in the analyses of several variable amino acid sites within the domains suggesting their vital role in the pathogenesis of the fungi. Further, the online server ConSurf implied that mostly, the highly conserved residues of the domains were functional and exposed on the surface of the active site, making it an easy target for the drugs. Consequently, variable analysis of functional domains of target implicated the importance of target specific drug discovery for the treatment of invasive fungal infections or mycoses.
| S-EPMC3124802 | biostudies-literature
Project description:Glucosamine 6-phosphate synthase converts fructose-6P into glucosamine-6P or glucose-6P depending on the presence or absence of glutamine. The isomerase activity is associated with a 40-kDa C-terminal domain, which has already been characterized crystallographically. Now the three-dimensional structures of the complexes with the reaction product glucose-6P and with the transition state analog 2-amino-2-deoxyglucitol-6P have been determined. Glucose-6P binds in a cyclic form whereas 2-amino-2-deoxyglucitol-6P is in an extended conformation. The information on ligand-protein interactions observed in the crystal structures together with the isotope exchange and site-directed mutagenesis data allow us to propose a mechanism of the isomerase activity of glucosamine-6P synthase. The sugar phosphate isomerization involves a ring opening step catalyzed by His504 and an enolization step with Glu488 catalyzing the hydrogen transfer from C1 to C2 of the substrate. The enediol intermediate is stabilized by a helix dipole and the epsilon-amino group of Lys603. Lys485 may play a role in deprotonating the hydroxyl O1 of the intermediate.
| S-EPMC2144271 | biostudies-other
Project description:BackgroundPresently available chemical based synthetic preservative have emerged with various side effects, so the aspiration of natural and side effect free novel preservative has been greatly increased. As the natural preservative exhibit poor side effect with improved preservative efficacy. The recent development in computational studies leads advancement in drug designing and discovery of novel glucosamine-6-phosphate synthase (G-6-P synthase) inhibition based natural antimicrobial preservatives. Here, selected aesculin derivatives were screened for G-6-P synthase inhibition via docking study and evaluated for antioxidant, antimicrobial, preservative efficacy as well stability study.ResultsModified aesculin derivatives were designed, synthesized and showed potent G-6-P synthase inhibition with remarkable antimicrobial, antioxidant, preservative efficacy and stability study. The molecular docking with target pdb id 1moq from G-6-P synthase resulted with better dock score and energy for compound 1 as compared to standard drugs streptomycin, ciprofloxacin, ampicillin and fluconazole, that supported the wet lab results. Among the synthesized compounds, the compound 1 possessed good antioxidant activity as compared to standard L-ascorbic acid. The resultant data for antimicrobial activity of aesculin derivatives revealed compound 1 as the most potent antimicrobial compound as compared to the standard drugs streptomycin, ciprofloxacin, ampicillin and fluconazole. While compound 2 showed better antimicrobial activity as compared to streptomycin, ciprofloxacin, ampicillin. The preservative efficacy test for compound 1 in aloe vera juice and white lotion USP has been showed the log CFU/mL values within the prescribed limit of USP standard and results were comparable to standard sodium benzoate, ethyl paraben and propyl paraben. Compound 1 has been found to be within prescribed limit of stability study over six month.ConclusionCompound 1 showed the potent G-6-P synthase inhibitory, antioxidant, antimicrobial, preservative efficacy and stability study results as compared to standard drugs taken. The results have found comparable to molecular docking results, and this final compound may be used as new preservatives for food and pharmaceutical products. Moreover, the mechanistic insight into the docking poses was also explored by binding interactions of aesculin derivatives inside the pdb id 1moq. These results also supported the results for novel synthesized G-6-P synthase inhibitors.
| S-EPMC8317424 | biostudies-literature
Project description:BackgroundSerratia marcescens becomes an apparent nosocomial pathogen and causes a variety of infections. S. marcescens possess various virulence factors that are regulated by intercellular communication system quorum sensing (QS). Targeting bacterial virulence is a proposed strategy to overcome bacterial resistance. Sitagliptin anti-QS activity has been demonstrated previously and we aimed in this study to investigate the effects of antidiabetic drugs vildagliptin and metformin compared to sitagliptin on S. marcescens pathogenesis.MethodsWe assessed the effects of tested drugs in subinhibitory concentrations phenotypically on the virulence factors and genotypically on the virulence encoding genes' expressions. The protection of tested drugs on S. marcescens pathogenesis was performed in vivo. Molecular docking study has been conducted to evaluate the interference capabilities of tested drugs to the SmaR QS receptor.ResultsVildagliptin reduced the expression of virulence encoding genes but did not show in vitro or in vivo anti-virulence activities. Metformin reduced the expression of virulence encoding genes and inhibited bacterial virulence in vitro but did not show in vivo protection. Sitagliptin significantly inhibited virulence factors in vitro, reduced the expression of virulence factors and protected mice from S. marcescens. Docking study revealed that sitagliptin is more active than metformin and fully binds to SmaR receptor, whereas vildagliptin had single interaction to SmaR.ConclusionThe downregulation of virulence genes was not enough to show anti-virulence activities. Hindering of QS receptors may play a crucial role in diminishing bacterial virulence.
| S-EPMC8105466 | biostudies-literature