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Fema Based Drug Design for Potentiation of Β-Lactam Antibiotics

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Fema Based Drug Design for Potentiation of Β-Lactam Antibiotics FemA based drug design for potentiation of β-lactam antibiotics against Methicillin resistant Staphylococcus aureus A thesis submitted in fulfillment of the requirement for the award of the degree of DOCTOR OF PHILOSOPHY IN BIOTECHNOLOGY Submitted By DIVYA SINGHAL (Reg. No. 900900020) Under the supervision of Dr. SANJAI SAXENA Professor Department of Biotechnology Thapar Institute of Engineering and Technology, Patiala-147004, Punjab December, 2017 Scanned by CamScanner Scanned by CamScanner Scanned by CamScanner Scanned by CamScanner Scanned by CamScanner Dedicated to My Family Publications 1. Singhal D. and Saxena S. (2015): Screening and toxicity analysis of catechin isomers against FemA protein. Indian journal of pharmaceutical sciences, 77(6): 758. (PMCID: PMC4778237). 2. Singhal D. and Saxena, S., (2017): Catechin gallate a promising resistance modifying candidate to potentiate β-lactam antibiotics to overcome resistance in Staphylococcus aureus. Current Medicine Research and Practice, 7:224–228. 3. Singhal D., and Saxena S Identification Method of and aureus. Annual Research and Review in Biology, (Paper in Communication). Table of Contents . List of tables i-ii . List of figures iii-vi . Executive Summary Sr. No. Chapter Page No. 1. Introduction 1–9 2. Present approach and Hypothesis 10-11 2.1 Hypothesis 10 2.2 Objective 10-11 3. Review of Literature 12-31 3.1 Pathogenicity of Staphylococcus aureus 12 3.1.1 Virulence Determinants 12 3.2 Target Sites for Antibiotics 14 3.2.1. Cell wall Synthesis Inhibitors 14 3.2.2. Translation Inhibitors 15 3.2.3. DNA Synthesis Inhibitors 16 3.3 Resistance Mechanism of MRSA 17 3.4 Resistance Modifying Agents (MA’s) 18 3.4.1 Acting on modified target site of antimicrobial agents 18 3.4.2 As membrane permeabilizing agents 18 3.4.3 Inhibitors of enzymes that inactivate antibiotics 19 3.4.4 Inhibitors of efflux pumps 19 3.5 Mechanism of Modulating Methicillin Resistance 20 3.6 Computational Methods in Drug Design 21 3.7 Methods of Determining Resistance 25 3.7.1. Detection of genes 25 3.7.2. MIC Assay 26 3.7.3. Checkerboard and FIC Index 28 3.7.4. Time kill curve 29 3.8 Analytical Techniques 30 3.8.1. High-Performance Liquid Chromatography (HPLC) 30 3.8.2. Mass Spectrometry (MS) 31 4 MATERIALS AND METHODS 33-46 4.1 Structure Databases 33 4.2. Identifications of Binding Sites 33 4.2.1 SiteHound 33 4.2.2. QsiteFinder 33 4.2.3. Pocket Finder 34 4.2.4 CASTp (Computed atlas of surface topography of proteins) 34 4.3 Docking Tools 34 4.3.1 Autodock Vina 34 4.3.2 Dock 35 4.4 In silico Interaction and Toxicity Studies 36 4.4.1 Toxicological studies 36 4.4.2. Lipinski filters 36 4.5 Culture repository 37 4.5.1 Procurement of test isolates 37 4.5.2 Maintenance of cultures 37 4.5.3 Preparation of 0.5 McFarland turbidity standard (CLSI, 1997) 37 4.5.4: Growth curve studies of test isolate 38 4.6 mecA and femA characterization of the test isolates 39 4.6.1 Isolation of bacterial genomic DNA 39 4.6.2 PCR for the detection of mec A and femA 40 4.7 In vitro susceptibility studies of S. aureus isolates 41 4.7.1 In vitro microbroth dilution assay: determination of MIC 41 4.7.2 Checkerboard Assay and FIC Index 42 4.7.3 Time Kill Assay of Synergistic Formulations 45 4.8 Evaluation of functional Expression of FemA protein 45 4.8.1 Peptidoglycan (PGN) cell wall extraction 45 4.8.2 Derivatization of Samples 46 4.8.3 LC‐MS Analysis 47 5. Results 48-87 5.1 Structure Databases 48 5.2. Identification of Binding Sites 53 5.2.1. SiteHound 53 5.2.2. Q-SiteFinder 54 5.2.3. PocketFinder 55 5.2.4. CASTp 56 5.3. Docking Tools 57 5.3.1 AutoDock Vina 57 5.3.2. Dock 58 5.4 Interaction and Toxicity studies 59 5.4.2 Toxicological studies 61 5.4.3 Lipinski filters 62 5.5 Test Cultures 63 5.5.1 Growth curve studies of test isolates 63 5.6 mecA and femA characterization of the test isolates 64 5.7 Evaluation of microbial activity of S. aureus isolates 65 5.7.1 In vitro microbroth dilution assay: determination of MIC 65 5.7.2 Checkerboard : FIC INDEX Assay 67 5.7.3 Time Kill Curve 76 5.8 Evaluation of FemA protein functional Expression 81 5.8.1 nLC-MS 81 6 Discussion 88-99 7 Conclusion 100 8 Bibliography 101-129 9 Appendix 130-139 List of Table Table No. Table Title Page No. Materials and Methods 4.8.2.1 nLC-MS samples with nLC-Ms code and their description 47 Results 5.1 Summary of Catechin isomers 51-52 5.2 Details of active sites in L-domain as predicted by SiteHound tool 53 5.3 Details of active sites in L-domain as predicted by Q-SiteFinder tool 54 5.4 Details of active sites in L-domain as predicted by PocketFinder tool 55 5.5 Details of active sites in L-domain as predicted by CASTp tool 56 5.6 Results predicted by AutoDock Vina 57 5.7. Results predicted by Dock 58 5.8 Toxicity results predicted by Osiris 61 5.9 Lipinski results 62 5.10. MIC of S. aureus all three strains w.r.t. antibiotic oxacillin, penicillin and test 67 compound CG 5.11 FIC INDEX of S. aureus NCTC 6571 with antibiotic oxacillin and test compound CG 69 5.12 FIC INDEX of S. aureus MTCC 737 with antibiotic oxacillin and test compound CG 70 5.13 FIC INDEX of S. aureus MTCC 96 with antibiotic oxacillin and test compound CG 71 5.14 FIC INDEX of S. aureus NCTC 6571 with antibiotic penicillin and test compound CG 72 5.15 FIC INDEX of S. aureus MTCC 737 with antibiotic penicillin and test compound CG 73 5.16 FIC INDEX of S. aureus MTCC 96 with antibiotic penicillin and test compound CG 74 5. 17. Summary of FIC Values for all three strains S. aureus for antibiotic oxacillin (O) 75 and penicillin (P) with Catechin Gallate (CG) i 5.18 Comparative kill kinetics of S. aureus NCTC 6571 with absence of any antibiotic, 77 in presence of oxacillin, CG and formulation of oxacillin and CG 5.19 Comparative kill kinetics of S. aureus NCTC 6571 with absence of any antibiotic, 77 in presence of penicillin, CG and formulation of penicillin and CG 5.20 Comparative kill kinetics of S. aureus MTCC 737 with absence of any antibiotic, 78 in presence of oxacillin, CG and formulation of oxacillin and CG 5.21 Comparative kill kinetics of S. aureus MTCC 96 with absence of any antibiotic, 78 in presence of oxacillin, CG and formulation of oxacillin and CG 5.22 nLC-MS Results Summary (APPENDIX) 135 ii List of Figures Fig. No. Figure Legend Page No. Introduction 1.1 2D Structure of β-lactam antibiotics 2 1.2. 2D Structure of 5th generation of β lactam antibiotics and Texiobactin 5 1.3. 2D structures of resistance modifying agents of β-lactamase producing MRSA 5 1.4. Schematic representation of an idealized cell-wall peptidoglycan of S. aureus and 7 its fem-deletion mutants. 1.5. 2D structures of resistance modifying agents of β-lactam antibiotics from plants 9 Review of Literature 3.1.1.1. Pathogenicity of S. aureus, with structural and secreted products 13 3.6.1 Citation percentage of most common docking programs period 23 3.6.2. Evolution of the number of citations/year for the 7 most cited protein-ligand docking 23 programs over the period 2001-2011. Materials and Methods 4.1 Docking grid prepared by AutoDock Vina 35 4.2 Config File (APPENDIX) 130 4.3 INSPH File (APPENDIX) 130 4.4 OUTSPH File (APPENDIX) 130-132 4.5. Showsph.in File (APPENDIX) 132 4.6. Showbox.in File (APPENDIX) 133 4.7. Grid.in File (APPENDIX) 133 4.7.1 Microtitre plate template for in vitro microbroth dilution assay for determination of MIC42 4.7.2 Microtitre plate template for checkerboard assay for determination of FIC 44 iii 4.8. Rigid.in File (APPENDIX) 134 Results 5.1 Structure of S.aureus in two domains (a) Cartoon View (b) Surface View having L- 49 shaped (white) substrate binding domain 5.2 S. aureus FemA protein sequence and secondary structure in three domains 50 5.3 Active sites predicted by SiteHound tool 53 5.4 Active sites predicted by Q-SiteFinder tool 54 5.5 Active sites predicted by PocketFinder tool 55 5.6 Active sites predicted by CASTp tool 56 5.7 AutoDock Vina results: FemA protein complex with ligand Catechin Gallate and Catechin 59 5.8 UCSF Dock results: FemA protein complex with ligand Catechin Gallate 59 5.9 Interaction of Catechin Gallate with different residues of FemA protein given by 60 LIGPLOT+ tool 5.10 Growth Curve of S. aureus strains 64 5.11 (a) Screening of staphylococcal isolates for the presence of mecA gene with 533 bp 65 amplicon and (b) femA gene with 132 bp amplicon as a marker for methicillin resistance 5.12 Microbroth dilution results of S. aureus NCTC 6571, S. aureus MTCC 737 66 and S. aureus MTCC 96 with antibiotic Oxacillin 5.13 Microbroth dilution results of S. aureus NCTC 6571, S. aureus MTCC 737 66 and S. aureus MTCC 96 with antibiotic Penicillin 5.14 Microbroth dilution results of S.
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