title: Investigating the therapeutic potential of herbal leads against drug resistant Listeria monocytogenes by computational virtual screening and in vitro assays.
abstract: Listeria monocytogenes, a Gram-positive opportunistic food-borne pathogen, naturally resistant to many antibiotics and acquired resistance may be a concern in the nearer future. Hence, there is a scope for screening of novel therapeutic agents and drug targets, toward the treatment of fatal listeria infections. The SecA homologs, SecA1 and SecA2 are the essential components of the general secretion (Sec) pathway, a specialised protein export system, present in L. monocytogenes. This study evaluates the use of botanicals against L. monocytogenes MTCC 1143 by considering SecA proteins as probable drug targets by high-throughput screening approaches. The 3D structure of SecA proteins with good stereochemical validity was generated by comparative modelling. The druglikeness and pharmacokinetic properties of 97 phytoligands identified through the extensive literature survey were predicted for druglikeness and ADMET properties. The inhibitory properties of best candidates were studied by molecular docking. The effect of the selected candidate molecules were further analysed in vitro well diffusion and cell aggregation assays. The antibiotic sensitivity profiling applied to L. monocytogenes MTCC 1143 using clinically relevant antibiotics showed that the bacteria became drug resistant to many tested antibiotics. The virtual screening suggested that .05 M cinnamic aldehyde from Cinnamomum camphora and 1, 2-Epoxycyclododecane from Cassia auriculata were identified as potential SecA inhibitors. The well diffusion assays suggested that the selected herbal substances have antibacterial activities. Further, preliminary validation suggested that incorporation of cinnamic aldehyde and methanolic or ethyl acetate extract of C. auriculata in broth medium shows growth reduction, misassembly and cell aggregation. This indicates the inhibition of SecA targets.
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Sinosh
authors.initials: S
authors.lastname: Skariyachan
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Anitha
authors.initials: A
authors.lastname: Pachiappan
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Jeenu
authors.initials: J
authors.lastname: Joy
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Rupam
authors.initials: R
authors.lastname: Bhaduri
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Imlimaong
authors.initials: I
authors.lastname: Aier
authors.affiliation: a R & D Centre, Department of Biotechnology Engineering , Dayananda Sagar Institutions , Bangalore , Karnataka 560 078 , India.|b Department of Biotechnology , Visvesvaraya Technological University , Belgavi , India.
authors.forename: Kiran S
authors.initials: KS
authors.lastname: Vasist
mesh_terms: D000171:Acrolein / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D027424:Cinnamomum / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D007700:Kinetics; D008024:Ligands; D008089:Listeria monocytogenes / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000737:chemistry* / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D028321:Plant Preparations / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D000069816:SEC Translocation Channels; D000081416:SecA Proteins
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D008024:Ligands; D026901:Membrane Transport Proteins; D028321:Plant Preparations; D000069816:SEC Translocation Channels; D000171:Acrolein; D000251:Adenosine Triphosphatases; D000081416:SecA Proteins; C012843:cinnamaldehyde
keywords: 1, 2-epoxycyclododecane; Listeria monocytogenes MTCC 1143; SecA proteins; antibiotic sensitivity profiling; cell aggregation; cinnamic aldehyde; molecular docking; phytoligands; well diffusion assays