The Discovery of Antibacterial Natural Compound Based on Peptide Deformylase

Background: In recent years, Staphylococcus aureus have developed resistance to medicines used for the treatment of human infections. Therefore, the search for antibacterial agents of high potency against Staphylococcus aureus is of great concern. Peptide deformylase (PDF), a metalloprotease catalyzing the removal of a formyl group from newly synthesized proteins, has been considered to be an important antibacterial drug target. Objective: To discover novel antibacterial drugs based on Staphylococcus aureus peptide deformylase. Method: PDF-based virtual screening of compounds from Traditional Chinese Medicine Database@Taiwan was performed by Sybyl X2.1 Surflex dock software. Compounds which possess high docking score were used for the following antibacterial experiments to evaluate their antibacterial activities. Kanamycin was also used in the antibacterial experiment as a control substance in the assay. Furthermore, molecular docking studies was applied to elucidate binding interaction between some compounds and PDF. In silico pharmacokinetic and toxicity prediction was explored to explain the reasons why these compounds might stand good chance of providing some pharmaceutical benefits. Results: Gentiopicroside, protosappanin B, dihydromyricetin and cryptochlorogenic acid with high docking score were used for our subsequent antibacterial assays. The Minimum Inhibitory Concentration (MIC) of kanamycin and gentiopicroside were 0.008 mg·mL-1 and 0.431 mg·mL-1, respectively, other three compounds, protosappanin B, dihydromyricetin and cryptochlorogenic acid have close MIC value of 0.50 mg·mL-1. Conclusion: Dihydromyricetin, with the MIC value of 0.50 mg·mL-1 and relatively high drug score of 0.82, may serve as a novel antibacterial lead compound.

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Peptide Deformylase as an Antibacterial Drug Target: Assays for Detection of Its Inhibition in Escherichia coli Cell Homogenates and Intact Cells

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.4.1053-1057.2001 ◽

2001 ◽

Vol 45 (4) ◽

pp. 1053-1057 ◽

Cited By ~ 10

Author(s):

Christian M. Apfel ◽

Stefan Evers ◽

Christian Hubschwerlen ◽

Wolfgang Pirson ◽

Malcolm G. P. Page ◽

...

Keyword(s):

Drug Target ◽

Peptide Deformylase ◽

Translation System ◽

Antibacterial Drug ◽

Bacterial Cells ◽

Methionine Aminopeptidase ◽

Intact Cells ◽

Physiological Conditions ◽

A Cell ◽

Antibacterial Drug Target

ABSTRACT An assay was developed to determine the activity of peptide deformylase (PDF) inhibitors under conditions as close as possible to the physiological situation. The assay principle is the detection of N-terminal [35S]methionine labeling of a protein that contains no internal methionine. If PDF is active, the deformylation of the methionine renders the peptide a substrate for methionine aminopeptidase, resulting in the removal of the N-terminal methionine label. In the presence of a PDF inhibitor, the deformylation is blocked so that the N-formylated peptide is not processed and the label is detected. Using this assay, it is possible to determine the PDF activity under near-physiological conditions in a cell-free transcription-translation system as well as in intact bacterial cells.

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Antibacterial Activity of the Root Extracts of Garcinia Kola Against MDR Staphylococcus Aureus : Invitro and Insilico Studies

10.26434/chemrxiv.13649606.v1 ◽

2021 ◽

Author(s):

Abdulbasit Haliru Yakubu ◽

Muhammad Mustapha Muhammad

Keyword(s):

Staphylococcus Aureus ◽

Binding Pocket ◽

Docking Studies ◽

Trna Synthetase ◽

Root Extract ◽

Antibacterial Drug ◽

Economic Implication ◽

Amino Acid Residues ◽

Garcinia Kola ◽

Staph Aureus

MDR Staphylococcus aureus is an important bacteria with clinical and economic implication. Plants including Garcinia kola provides bioactive principles with diverse structural and biological features.. The n-Butanol fraction of G.kola root extract recorded the highest activity against MDR staph aureus (18.50±0.41) compared to the chloroform (10.00±2.12) and methanol (8.166±0.62) extarct, with no activity recorded with the n-Hexane extract. Analysis of this fraction on GC-MS recorded 14 phytoconstituents with varying structural composition; containing important scaffolds & motifs of benzoquinone, <a href="https://pubchem.ncbi.nlm.nih.gov/compound/imidazo[1,2-a]pyridine">imidazo[1,2-a]pyridine</a>, Chlorocarbazole and azetidine that present key pharmaceuticals as antibiotic and for drug development. Further inslico molecular docking studies of these compounds on antibacterial drug target; Tyrosyl-tRNA synthetase (PDB 1JIJ) from MDR staph aureus was documented. 9 compounds (CID_619544, CID_619583, CID_5732, CID_616643, CID_622021, CID_ 616496, CID_590350, CID_16486 and CID_66747) had good binding scores ranging from -4.63 to -7.08 kcal/mol; with CID_590350 having the highest score. The compounds formed various bonding with the 1JIJ amino acid residues including H-bond, van der waal and π interactions. CID_16486 and CID_66747 bind to the most active binding pocket (Drug score: 0.82 &0.72) while CID_619583 tend to bind outside the active binding pocket. They also have good pharmacokinetic and toxicity profile. Therefore, these compounds are considered as suitable prospective antibiotics against MDR Staphylococcus aureus after successful invitro and insilico experimental validation.

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Interaction of 2, 5-di-tert-butyl-1, 4-Benzoquinone with Selected Antibacterial Drug Target Enzymes by In silico Molecular Docking Studies

American Journal of Drug Discovery and Development ◽

10.3923/ajdd.2013.200.205 ◽

2013 ◽

Vol 3 (3) ◽

pp. 200-205

Author(s):

J. Vinay Gopal ◽

K. Kannabiran

Keyword(s):

Molecular Docking ◽

In Silico ◽

Drug Target ◽

Docking Studies ◽

Antibacterial Drug ◽

Molecular Docking Studies ◽

Tert Butyl ◽

In Silico Molecular Docking ◽

Antibacterial Drug Target

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Peptide Deformylase as an Antibacterial Drug Target: Target Validation and Resistance Development

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.45.4.1058-1064.2001 ◽

2001 ◽

Vol 45 (4) ◽

pp. 1058-1064 ◽

Cited By ~ 89

Author(s):

Christian M. Apfel ◽

Hans Locher ◽

Stefan Evers ◽

Béla Takács ◽

Christian Hubschwerlen ◽

...

Keyword(s):

Antibacterial Activity ◽

Proteome Analysis ◽

Peptide Deformylase ◽

Antibacterial Drug ◽

Resistance Development ◽

E Coli ◽

Development Of Resistance ◽

Optimal Target ◽

Antibacterial Drug Target ◽

Increased Susceptibility

ABSTRACT New inhibitors of peptide deformylase (PDF) which are very potent against the isolated enzyme and show a certain degree of antibacterial activity have recently been synthesized by our group. Several lines of experimental evidence indicate that these inhibitors indeed interfere with the target enzyme in the bacterial cell. (i) The inhibition ofEscherichia coli growth could be counteracted by overexpression of PDF from different organisms, including E. coli, Streptococcus pneumoniae, and Haemophilus influenzae. Conversely, reduced expression of PDF in S. pneumoniae resulted in an increased susceptibility to the inhibitors. (ii) Proteome analysis on two-dimensional gels revealed a shift for many proteins towards lower pI in the presence of PDF inhibitors, as would be expected if the proteins still carry theirN-formyl-Met terminus. (iii) PDF inhibitors show no antimicrobial activity against E. coli under conditions that make growth independent of formylation and deformylation. The antibacterial activity in E. coli was characterized as bacteriostatic. Furthermore, the development of resistance in E. coli was observed to occur with high frequency (10−7). Resistant mutants show a reduced growth rate, and DNA sequence analysis revealed mutations in their formyl transferase gene. Taking all these aspects into account, we conclude that PDF may not be an optimal target for broad-spectrum antibacterial agents.

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Production of New Antibacterial 4-Hydroxy-α-Pyrones by a Marine Fungus Aspergillus niger Cultivated in Solid Medium

Marine Drugs ◽

10.3390/md17060344 ◽

2019 ◽

Vol 17 (6) ◽

pp. 344 ◽

Cited By ~ 8

Author(s):

Lijian Ding ◽

Lu Ren ◽

Shuang Li ◽

Jingjing Song ◽

Zhiwen Han ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Aspergillus Niger ◽

Spectroscopic Data ◽

Pathogenic Bacteria ◽

Methicillin Resistant Staphylococcus Aureus ◽

Inhibitory Concentration ◽

Solid Medium ◽

Antibacterial Activities ◽

Marine Fungus ◽

Mic Value

Four 4-hydroxy-α-pyrones including three new ones named nipyrones A–C (1–3) together with one known analogue germicidin C (4) were discovered from a marine sponge-derived fungus Aspergillus niger cultivated in a solid rice culture. Their structures and absolute configurations were elucidated through a combination of spectroscopic data and electronic circular dichroism (ECD) calculations as well as comparison with literature data. Compounds 1–4 were evaluated for their antibacterial activities against five pathogenic bacteria (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, methicillin-resistant Staphylococcus aureus, and Mycobacterium tuberculosis). Compound 3 showed promising activity against S. aureus and B. subtilis, with minimum inhibitory concentration (MIC) values of 8 μg/mL and 16 μg/mL, respectively, and displayed weak antitubercular activities against M. tuberculosis, with MIC value of 64 μg/mL, while compounds 1 and 2 exhibited moderate antibacterial efficacy against four pathogenic bacteria with MIC values of 32–64 μg/mL.

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Syzygium jambosDisplayed Antibacterial and Antibiotic-Modulating Activities against Resistant Phenotypes

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/5124735 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12

Author(s):

Brice E. N. Wamba ◽

Paul Nayim ◽

Armelle T. Mbaveng ◽

Igor K. Voukeng ◽

Joachim K. Dzotam ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Synergistic Effects ◽

Enterobacter Aerogenes ◽

Antibacterial Activities ◽

Bark Extract ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Syzygium Jambos ◽

Broth Microdilution Method ◽

Mic Value

The present study was designed to evaluate the antibacterial activities of methanol extracts of bark and leaves ofSyzygium jambos, as well as their synergistic effects with selected antibiotics against drug-resistant Gram-positive and Gram-negative bacteria. The crude extracts were subjected to qualitative phytochemical screening; broth microdilution method was used for antibacterial assays. Phytochemical studies indicate that leaves and bark extracts contained polyphenols, anthraquinones, tannins, and steroids. Extract of the leaves was active against all the 26 strains ofStaphylococcus aureusand all the 21 strains of Gram-negative bacteria tested, within the minimum inhibitory concentration (MIC) range of 32–512 μg/mL. The lowest MIC value of 32 μg/mL was obtained with extract of the leaves againstStaphylococcus aureusMRSA9 strain. In Gram-negative bacteria, the lowest MIC value of 64 μg/mL was also obtained againstEnterobacter aerogenesEA294 andKlebsiella pneumoniaeK24 strains. AgainstS. aureusstrains, antibiotic-modulating activity of extracts at MIC/2 towards more than 70% of the tested strains was obtained when leaves and bark extracts were tested in association with chloramphenicol (CHL). This was also the case when leaves extract was combined with CHL, kanamycin (KAN), tetracycline (TET), and erythromycin (ERY) and when bark extract was combined with ciprofloxacin (CIP), TET, and ERY against Gram-negative bacteria. In conclusion, this study demonstrated thatSyzygium jamboshas antibacterial and antibiotic-modulating activities.

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Synthesis, Molecular Docking Studies and Antibacterial Activities of Novel Monocationic Indole-benzimidazole Derivatives

Medicinal Chemistry ◽

10.2174/1573406416666200420080459 ◽

2020 ◽

Vol 16 ◽

Author(s):

Zeynep Ates-Alagoz ◽

Mehmet Murat Kisla ◽

Hakan Goker ◽

Sulhiye Yildiz

Keyword(s):

Staphylococcus Aureus ◽

Molecular Docking ◽

Pyruvate Kinase ◽

Metabolic Flux ◽

Antibacterial Properties ◽

Antibacterial Activities ◽

Docking Studies ◽

Log P ◽

Methicillin Resistant ◽

Metabolic Flux Distribution

Background: Finding efficient therapy against hospital-acquired MRSA infections has become rather important in the last decade. To this end, inhibition of the enzyme pyruvate kinase (PK) is being investigated for antibacterial activity, since this enzyme controls energy generation and metabolic flux distribution. Our main scaffold consists of benzimidazole and indole rings fused together. Both rings are famous for antibacterial properties and promising anti-MRSA compounds include indole ring. Methods: Several 1-substituted-2-(1H-indol-3-yl)-N-substituted-1H-benzimidazole-5-carboxamidine analogues were developed, synthesized and their antibacterial activities were evaluated against Staphylococcus aureus (ATCC 25923), Methicillin resistant Staphylococcus aureus (MRSA) (ATCC 43300), and Staphylococcus epidermidis (ATCC 12228) by using tube dilution method. Molecular docking analysis with a characteristic protein called MRSA- Pyruvate Kinase has been conducted for the assessment of the activities of our compounds against Methicillin-resistant S.aureus (MRSA). Results: Among all the tested compounds, the most potent compound 36 had MIC values as 3.12, 3.12 and 6.25 µg/mL against S. aureus, Methicillin-resistant S. aureus (MRSA), and S. epidermidis, respectively. This compound had much better docking energy value than standard ampicillin and also created the link between two residues in different monomers of PK. Discussion: . This approach of using indol-amidine conjugate systems as anti-MRSA agents may include MRSA-PK as potential target. To further increase the affinity, some other H-bonding parts may be added. By doing so, another bridge with Ile361 residues on both sides can be created. Our compounds tend to violate log P limit of Lipinski, therefore some optimizations with formulation can be made. Conclusion: This study mainly includes the design, synthesis and optimization of indole-benzimidazole-amidine derivatives. Docking studies confirmed our results, since our most potent hit compound 36 created the necessary interactions between two chains of MRSA-PK. Further optimization can be considered to increase drug ability.

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In Silico Screening of Potential Inhibitors of the Epidermal Growth Factor Receptor Kinase using Benzimidazole, Benzoxazole, Imidazole, and Tetrazole Derivatives

Journal of Pharmaceutical Research International ◽

10.9734/jpri/2021/v33i50b33428 ◽

2021 ◽

pp. 60-71

Author(s):

Subramaniyan Arulmurugan ◽

Helen P. Kavitha ◽

Jasmine P. Vennila

Keyword(s):

Molecular Docking ◽

Tyrosine Kinase ◽

In Silico ◽

Heterocyclic Compounds ◽

Docking Studies ◽

Tyrosine Kinase Receptor ◽

Binding Interaction ◽

Docking Score ◽

Molecular Docking Studies ◽

Egfr Tyrosine Kinase

Background: Small molecule compounds are docked into receptor binding sites and the binding affinity of the complex is calculated using the structure-based drug design technique. Precise and quick docking processes, as well as the capacity to examine binding geometries and interactions, are required for a full knowledge of the structural principles that influence the strength of a protein/ligand complex. The present work deals with in-silico molecular docking studies of some heterocyclic compounds such as benzoxazole, benzimidazole, imidazole and tetrazole against the EGFR tyrosine kinase receptor. Methodology: Molecular docking studies of some heterocyclic compounds such as benzoxazole, benzimidazole, imidazole and tetrazole against the EGFR tyrosine kinase receptor using Schrodinger LLC (Maestro 9.2) software. Results: Our in silico observations reveal that, all the selected heterocyclic compounds (1-8) show good binding interaction and good docking score against selected target enzyme. Out of eight compounds selected for the study two compounds compound 3 and 7 shows higher glide score. Compound 3 binded to ASP855 with a docking score of −11.20 kcal/mol. Compound 7 binded to ASP855 with a docking score of −11.56kcal/mol. Conclusion: Docking results revealed that compounds (1-8) interact with EGFR kinase receptor active site. Among the compounds, compound 7 has shown the highest glide score of -11.56 kcal/mol.

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Characterization of peptide deformylase homologues from Staphylococcus epidermidis

Microbiology ◽

10.1099/mic.0.038174-0 ◽

2010 ◽

Vol 156 (10) ◽

pp. 3194-3202 ◽

Cited By ~ 1

Author(s):

Penghui Lin ◽

Tiancen Hu ◽

Jian Hu ◽

Wenqi Yu ◽

Cong Han ◽

...

Keyword(s):

Staphylococcus Epidermidis ◽

Metal Binding ◽

Enzymic Activity ◽

Peptide Deformylase ◽

Antibacterial Drug ◽

Metal Binding Sites ◽

New Antibiotics ◽

Antibacterial Drug Target ◽

Drug Resistant Strains

The emergence of multi-drug-resistant strains of Staphylococcus epidermidis emphasizes the need to develop new antibiotics. The unique and essential role of the peptide deformylase (PDF) in catalysing the removal of the N-terminal formyl group from newly synthesized polypeptides in eubacteria makes it an attractive antibacterial drug target. In the present study, both deformylase homologues from S. epidermidis (SePDF-1 and SePDF-2) were cloned and expressed, and their enzymic activities were characterized. Co2+-substituted SePDF-1 exhibited much higher enzymic activity (k cat/K m 6.3×104 M−1 s−1) than those of Ni2+- and Zn2+-substituted SePDF-1, and SePDF-1 showed much weaker binding ability towards Ni2+ than towards Co2+ and Zn2+, which is different from PDF in Staphylococcus aureus (SaPDF), although they share 80 % amino-acid sequence identity. The determined crystal structure of SePDF-1 was similar to that of (SaPDF), except for differences in the metal-binding sites. The other deformylase homologue, SePDF-2, was shown to have no peptide deformylase activity; the function of SePDF-2 needs to be further investigated.

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