title: Synergy Potential of Indole Alkaloids and Its Derivative against Drug-resistant Escherichia coli.
abstract: Antibacterial and synergy potential of naturally occurring indole alkaloids (IA): 10-methoxy tetrahydroalstonine (1), isoreserpiline (2), 10 and 11 demethoxyreserpiline (3), reserpiline (4), serpentine (5), ajmaline (6), ajmalicine (7), yohimbine (8), and α-yohimbine (9) was evaluated using microbroth dilution assay. Further, α-yohimbine (9) was chemically transformed into six semisynthetic derivatives (9A-9F), and their antibacterial and synergy potential in combination with nalidixic acid (NAL) against E. coli strains CA8000 and DH5α were also evaluated. The IA 1, 2, 4, 5, 9 and the derivative 9F showed eightfold reduction in the MIC of NAL against the DH5α and four- to eightfold reduction against CA8000. These alkaloids also reduced MIC of another antibiotic, tetracycline up to 8folds, against the MDREC-KG4, a multidrug-resistant clinical isolate of E. coli. Mode of action study of these alkaloids showed efflux pumps inhibitory potential, which was supported by their in silico binding affinity and downregulation of efflux pump genes. These results may be of great help in the development of cost-effective antibacterial combinations for treating patients infected with multidrug-resistant Gram-negative infections.
authors.affiliation: Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.|School of Environmental Sciences, Babasaheb Bhimrao Ambedkar Central University, Vidya Vihar, Rae Bareli Road, Lucknow, 226025, India.
authors.forename: Gaurav Raj
authors.initials: GR
authors.lastname: Dwivedi
authors.affiliation: Medicinal Chemistry Department, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Shikha
authors.initials: S
authors.lastname: Gupta
authors.affiliation: Medicinal Chemistry Department, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Maurya
authors.affiliation: Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Shubhandra
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.affiliation: Biotechnology Division, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
authors.affiliation: Medicinal Chemistry Department, Central Institute of Medicinal and Aromatic Plants (CSIR-CIMAP), P.O.- CIMAP, Lucknow, 226015, India.
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D003198:Computer Simulation; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D004926:Escherichia coli / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005798:Genes, Bacterial / Q000187:drug effects; D006801:Humans; D026121:Indole Alkaloids / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D009268:Nalidixic Acid / Q000008:administration & dosage; D013329:Structure-Activity Relationship; D013752:Tetracycline / Q000008:administration & dosage
chemical_list: D000900:Anti-Bacterial Agents; D026121:Indole Alkaloids; D009268:Nalidixic Acid; D013752:Tetracycline
keywords: MDREC; antibacterial combination; indole alkaloids; nalidixic acid; semisynthetic derivatives; tetracycline