title: Phytol derivatives as drug resistance reversal agents.
abstract: Phytol was chemically transformed into fifteen semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with nalidixic acid against E. coli strains CA8000 and DH5α. The pivaloyl (4), 3,4,5-trimethoxybenzoyl (9), 2,3-dichlorobenzoyl (10), cinnamoyl (11), and aldehyde (14) derivatives of phytol ((2E,7R,11R)-3,7,11,15-tetramethyl-2-hexadecen-1-ol) were evaluated by using another antibiotic, tetracycline, against the MDREC-KG4 clinical isolate of E. coli. Derivative 4 decreased the maximal inhibitory concentration (MIC) of the antibiotics by 16-fold, while derivatives 9, 10, 11, and 14 reduced MIC values of the antibiotics up to eightfold against the E. coli strains. Derivatives 4, 9, 10, 11, and 14 inhibited the ATP-dependent efflux pump; this was also supported by their in silico binding affinity and down-regulation of the efflux pump gene yojI, which encodes the multidrug ATP-binding cassette transporter protein. This study supports the possible use of phytol derivatives in the development of cost-effective antibacterial combinations.
authors.affiliation: Medicinal Chemistry Department, P.O. CIMAP, Lucknow 226015 (India).
authors.forename: Harish C
authors.initials: HC
authors.lastname: Upadhyay
authors.forename: Gaurav R
authors.initials: GR
authors.lastname: Dwivedi
authors.forename: Sudeep
authors.initials: S
authors.lastname: Roy
authors.forename: Ashok
authors.initials: A
authors.lastname: Sharma
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
authors.forename: Santosh K
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D024881:Drug Resistance, Bacterial / Q000187:drug effects; D004926:Escherichia coli / Q000187:drug effects; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D062105:Molecular Docking Simulation; D010836:Phytol / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary
chemical_list: D018528:ATP-Binding Cassette Transporters; D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D010836:Phytol
keywords: antibiotics; docking studies; drug resistance; efflux pumps; phytol