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Rashmi Sharma - One of the best experts on this subject based on the ideXlab platform.
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Mechanism and Potential Inhibitors of GlmU: A Novel Target for Antimicrobial Drug Discovery.
Current Drug Targets, 2017Co-Authors: Rashmi Sharma, Inshad Ali KhanAbstract:BACKGROUND: Multidrug resistant Gram negative pathogens pose a persistent threat to the health care system and require investigation of new targets and molecules for the development of antibiotics to treat infections caused by MDR bacterial pathogens. OBJECTIVE: It is essential to work on multidisciplinary approaches and diverse strategies for developing new compounds acting on novel antibacterial targets. N-acetylglucosamine-1-Phosphateuridyltransferase/ glucosamine-1-Phosphate-Acetyltransferase (GlmU) is one such target which is involved in the synthesis of both peptidoglycan and Lipopolysaccharide in Gram negative and Gram positive bacteria making GlmU an attractive target for developing antibacterials. RESULTS: GlmU, as revealed by X- ray crystallographic studies, is made up of two domains connected by α helical arm; the N-terminal uridyltransferase domain resembles a dinucleotide Rossmann fold and the C- terminal Acetyltransferase domain adopts a left handed parallel β helix structure. The GlmU molecules are arranged in a trimeric array, the Acetyltransferase active site being formed at the junction of adjacent LβH domain. Many potent inhibitors of both the Acetyltransferase and uridyltransferase activity of GlmU have been identified. Inhibitors of the Acetyltransferase activity of GlmU include nonspecific thiol reactive agents, 2-phenylbenzofurans, arylamines and arylsulfonamides. A aminopiperidine based inhibitor has also been reported to inhibit uridyltransferase activity of hiGlmU. CONCLUSION: The present review provides an insight of the structure of GlmU and its reported inhibitors which make GlmU a potential target for drug designing. The GlmU is a promising target for drug discovery against Gram negative pathogens and future studies should focus on GlmU for the development of more potent compounds for treating Gram negative infections.
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identification and characterization of novel small molecule inhibitors of the Acetyltransferase activity of escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu
Applied Microbiology and Biotechnology, 2016Co-Authors: Rashmi Sharma, Chitra Rani, Reena Chib, Rukmankesh Mehra, Amit Nargotra, Vikrant Singh Rajput, Sunil Kumar, Samsher Singh, Parduman R Sharma, Inshad Ali KhanAbstract:This study aims at identifying novel chemical scaffolds as inhibitors specific to the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli GlmU, involved in the cell wall biosynthesis of Gram-negative organisms. A two-pronged approach was used to screen a 50,000 small-molecule library. Using the first approach, the library was in silico screened by docking the library against Acetyltransferase domain of E. coli GlmU studies. In the second approach, complete library was screened against Escherichia coli ATCC 25922 to identify the whole cell active compounds. Active compounds from both the screens were screened in a colorimetric absorbance-based assay to identify inhibitors of Acetyltransferase domain of E. coli GlmU which resulted in the identification of 1 inhibitor out of 56 hits identified by in silico screening and 4 inhibitors out of 35 whole cell active compounds on Gram-negative bacteria with the most potent inhibitor showing IC50 of 1.40 ± 0.69 μM. Mode of inhibition studies revealed these inhibitors to be competitive with AcCoA and uncompetitive with GlcN-1-P. These selected inhibitors were also tested for their antibacterial and cytotoxic activities. Compounds 5175178 and 5215319 exhibited antibacterial activity that co-related with GlmU inhibition. These compounds, therefore, represent novel chemical scaffolds targeting Acetyltransferase activity of E. coli GlmU.
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escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu inhibitory activity of terreic acid isolated from aspergillus terreus
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj MukherjeeAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
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Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus.
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj Mukherjee, Asha Chaubey, Inshad Ali KhanAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
Chitra Rani - One of the best experts on this subject based on the ideXlab platform.
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identification and characterization of novel small molecule inhibitors of the Acetyltransferase activity of escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu
Applied Microbiology and Biotechnology, 2016Co-Authors: Rashmi Sharma, Chitra Rani, Reena Chib, Rukmankesh Mehra, Amit Nargotra, Vikrant Singh Rajput, Sunil Kumar, Samsher Singh, Parduman R Sharma, Inshad Ali KhanAbstract:This study aims at identifying novel chemical scaffolds as inhibitors specific to the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli GlmU, involved in the cell wall biosynthesis of Gram-negative organisms. A two-pronged approach was used to screen a 50,000 small-molecule library. Using the first approach, the library was in silico screened by docking the library against Acetyltransferase domain of E. coli GlmU studies. In the second approach, complete library was screened against Escherichia coli ATCC 25922 to identify the whole cell active compounds. Active compounds from both the screens were screened in a colorimetric absorbance-based assay to identify inhibitors of Acetyltransferase domain of E. coli GlmU which resulted in the identification of 1 inhibitor out of 56 hits identified by in silico screening and 4 inhibitors out of 35 whole cell active compounds on Gram-negative bacteria with the most potent inhibitor showing IC50 of 1.40 ± 0.69 μM. Mode of inhibition studies revealed these inhibitors to be competitive with AcCoA and uncompetitive with GlcN-1-P. These selected inhibitors were also tested for their antibacterial and cytotoxic activities. Compounds 5175178 and 5215319 exhibited antibacterial activity that co-related with GlmU inhibition. These compounds, therefore, represent novel chemical scaffolds targeting Acetyltransferase activity of E. coli GlmU.
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escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu inhibitory activity of terreic acid isolated from aspergillus terreus
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj MukherjeeAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
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Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus.
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj Mukherjee, Asha Chaubey, Inshad Ali KhanAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
Inshad Ali Khan - One of the best experts on this subject based on the ideXlab platform.
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Mechanism and Potential Inhibitors of GlmU: A Novel Target for Antimicrobial Drug Discovery.
Current Drug Targets, 2017Co-Authors: Rashmi Sharma, Inshad Ali KhanAbstract:BACKGROUND: Multidrug resistant Gram negative pathogens pose a persistent threat to the health care system and require investigation of new targets and molecules for the development of antibiotics to treat infections caused by MDR bacterial pathogens. OBJECTIVE: It is essential to work on multidisciplinary approaches and diverse strategies for developing new compounds acting on novel antibacterial targets. N-acetylglucosamine-1-Phosphateuridyltransferase/ glucosamine-1-Phosphate-Acetyltransferase (GlmU) is one such target which is involved in the synthesis of both peptidoglycan and Lipopolysaccharide in Gram negative and Gram positive bacteria making GlmU an attractive target for developing antibacterials. RESULTS: GlmU, as revealed by X- ray crystallographic studies, is made up of two domains connected by α helical arm; the N-terminal uridyltransferase domain resembles a dinucleotide Rossmann fold and the C- terminal Acetyltransferase domain adopts a left handed parallel β helix structure. The GlmU molecules are arranged in a trimeric array, the Acetyltransferase active site being formed at the junction of adjacent LβH domain. Many potent inhibitors of both the Acetyltransferase and uridyltransferase activity of GlmU have been identified. Inhibitors of the Acetyltransferase activity of GlmU include nonspecific thiol reactive agents, 2-phenylbenzofurans, arylamines and arylsulfonamides. A aminopiperidine based inhibitor has also been reported to inhibit uridyltransferase activity of hiGlmU. CONCLUSION: The present review provides an insight of the structure of GlmU and its reported inhibitors which make GlmU a potential target for drug designing. The GlmU is a promising target for drug discovery against Gram negative pathogens and future studies should focus on GlmU for the development of more potent compounds for treating Gram negative infections.
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identification and characterization of novel small molecule inhibitors of the Acetyltransferase activity of escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu
Applied Microbiology and Biotechnology, 2016Co-Authors: Rashmi Sharma, Chitra Rani, Reena Chib, Rukmankesh Mehra, Amit Nargotra, Vikrant Singh Rajput, Sunil Kumar, Samsher Singh, Parduman R Sharma, Inshad Ali KhanAbstract:This study aims at identifying novel chemical scaffolds as inhibitors specific to the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli GlmU, involved in the cell wall biosynthesis of Gram-negative organisms. A two-pronged approach was used to screen a 50,000 small-molecule library. Using the first approach, the library was in silico screened by docking the library against Acetyltransferase domain of E. coli GlmU studies. In the second approach, complete library was screened against Escherichia coli ATCC 25922 to identify the whole cell active compounds. Active compounds from both the screens were screened in a colorimetric absorbance-based assay to identify inhibitors of Acetyltransferase domain of E. coli GlmU which resulted in the identification of 1 inhibitor out of 56 hits identified by in silico screening and 4 inhibitors out of 35 whole cell active compounds on Gram-negative bacteria with the most potent inhibitor showing IC50 of 1.40 ± 0.69 μM. Mode of inhibition studies revealed these inhibitors to be competitive with AcCoA and uncompetitive with GlcN-1-P. These selected inhibitors were also tested for their antibacterial and cytotoxic activities. Compounds 5175178 and 5215319 exhibited antibacterial activity that co-related with GlmU inhibition. These compounds, therefore, represent novel chemical scaffolds targeting Acetyltransferase activity of E. coli GlmU.
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Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus.
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj Mukherjee, Asha Chaubey, Inshad Ali KhanAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
Debaraj Mukherjee - One of the best experts on this subject based on the ideXlab platform.
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escherichia coli n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu inhibitory activity of terreic acid isolated from aspergillus terreus
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj MukherjeeAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
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Escherichia coli N-Acetylglucosamine-1-Phosphate-Uridyltransferase/Glucosamine-1-Phosphate-Acetyltransferase (GlmU) Inhibitory Activity of Terreic Acid Isolated from Aspergillus terreus.
Journal of Biomolecular Screening, 2016Co-Authors: Rashmi Sharma, Mallikharjuna Rao Lambu, Urmila Jamwal, Chitra Rani, Reena Chib, Priya Wazir, Debaraj Mukherjee, Asha Chaubey, Inshad Ali KhanAbstract:Secondary metabolite of Aspergillus terreus, terreic acid, is a reported potent antibacterial that was identified more than 60 years ago, but its cellular target(s) are still unknown. Here we screen its activity against the Acetyltransferase domain of a bifunctional enzyme, Escherichia coli N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). An absorbance-based assay was used to screen terreic acid against the Acetyltransferase activity of E. coli GlmU. Terreic acid was found to inhibit the Acetyltransferase domain of E. coli GlmU with an IC50 of 44.24 ± 1.85 µM. Mode of inhibition studies revealed that terreic acid was competitive with AcCoA and uncompetitive with GlcN-1-P. It also exhibited concentration-dependent killing of E. coli ATCC 25922 up to 4× minimum inhibitory concentration and inhibited the growth of biofilms generated by E. coli. Characterization of resistant mutants established mutation in the Acetyltransferase domain of GlmU. Terreic acid wa...
Ludovic Otterbein - One of the best experts on this subject based on the ideXlab platform.
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inhibitors of the Acetyltransferase domain of n acetylglucosamine 1 Phosphate uridylyltransferase glucosamine 1 Phosphate Acetyltransferase glmu part 2 optimization of physical properties leading to antibacterial aryl sulfonamides
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Suzanne Stokes, Oluyinka Green, Andrew R Mckenzie, Adam B Shapiro, Robert Albert, Ed T Buurman, Beth Andrews, Ludovic OtterbeinAbstract:Abstract A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC 50 D −1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13 .
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Inhibitors of the Acetyltransferase domain of N-acetylglucosamine-1-Phosphate-uridylyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). Part 2: Optimization of physical properties leading to antibacterial aryl sulfonamides.
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Suzanne S. Stokes, Oluyinka Green, Andrew R Mckenzie, Adam B Shapiro, Robert Albert, Ed T Buurman, Beth Andrews, Ludovic OtterbeinAbstract:Abstract A previously described aryl sulfonamide series, originally found through HTS, targets GlmU, a bifunctional essential enzyme involved in bacterial cell wall synthesis. Using structure-guided design, the potency of enzyme inhibition was increased in multiple isozymes from different bacterial species. Unsuitable physical properties (low Log D and high molecular weight) of those compounds prevented them from entering the cytoplasm of bacteria and inhibiting cell growth. Further modifications described herein led to compounds that possessed antibacterial activity, which was shown to occur through inhibition of GlmU. The left-hand side amide and the right-hand side sulfonamides were modified such that enzyme inhibitory activity was maintained (IC 50 D −1 to 3. Antibacterial activity in an efflux-pump deficient mutant of Haemophilus influenzae resulted for compounds such as 13 .
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inhibitors of Acetyltransferase domain of n acetylglucosamine 1 Phosphate uridyltransferase glucosamine 1 Phosphate Acetyltransferase glmu part 1 hit to lead evaluation of a novel arylsulfonamide series
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Oluyinka Green, Andrew R Mckenzie, Adam B Shapiro, Ludovic Otterbein, Haihong Ni, Arthur Patten, Suzanne Stokes, Robert Albert, Sameer Kawatkar, Jason BreedAbstract:A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the Acetyltransferase domain of N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40.
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Inhibitors of Acetyltransferase domain of N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). Part 1: Hit to lead evaluation of a novel arylsulfonamide series.
Bioorganic & Medicinal Chemistry Letters, 2012Co-Authors: Oluyinka Green, Andrew R Mckenzie, Adam B Shapiro, Ludovic Otterbein, Haihong Ni, Robert Albert, Sameer Kawatkar, Arthur D. Patten, Suzanne S. Stokes, Jason BreedAbstract:A novel arylsulfonamide-containing series of compounds represented by 1, discovered by highthroughput screening, inhibit the Acetyltransferase domain of N-acetylglucosamine-1-Phosphate-uridyltransferase/glucosamine-1-Phosphate-Acetyltransferase (GlmU). X-ray structure determination confirmed that inhibitor binds at the site occupied by acetyl-CoA, indicating that series is competitive with this substrate. This letter documents our early hit-to-lead evaluation of the chemical series and some of the findings that led to improvement in in-vitro potency against Gram-negative and Gram-positive bacterial isozymes, exemplified by compound 40.