title: Drug Resistance Reversal Potential of Ursolic Acid Derivatives against Nalidixic Acid- and Multidrug-resistant Escherichia coli.
abstract: As a part of our drug discovery program, ursolic acid was chemically transformed into six semi-synthetic derivatives, which were evaluated for their antibacterial and drug resistance reversal potential in combination with conventional antibiotic nalidixic acid against the nalidixic acid-sensitive and nalidixic acid-resistant strains of Escherichia coli. Although ursolic acid and its all semi-synthetic derivatives did not show antibacterial activity of their own, but in combination, they significantly reduced the minimum inhibitory concentration of nalidixic acid up to eightfold. The 3-O-acetyl-urs-12-en-28-isopropyl ester (UA-4) and 3-O-acetyl-urs-12-en-28-n-butyl ester (UA-5) derivatives of ursolic acid reduced the minimum inhibitory concentration of nalidixic acid by eightfold against nalidixic acid-resistant and four and eightfold against nalidixic acid-sensitive, respectively. The UA-4 and UA-5 were further evaluated for their synergy potential with another antibiotic tetracycline against the multidrug-resistant clinical isolate of Escherichia coli-KG4. The results showed that both these derivatives in combination with tetracycline reduced the cell viability in concentration-dependent manner by significantly inhibiting efflux pump. This was further supported by the in silico binding affinity of UA-4 and UA-5 with efflux pump proteins. These ursolic acid derivatives may find their potential use as synergistic agents in the treatment of multidrug-resistant Gram-negative infections.
authors.affiliation: Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Gaurav Raj
authors.initials: GR
authors.lastname: Dwivedi
authors.affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Anupam
authors.initials: A
authors.lastname: Maurya
authors.affiliation: Metabolic & Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Dharmendra Kumar
authors.initials: DK
authors.lastname: Yadav
authors.affiliation: Metabolic & Structural Biology, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Feroz
authors.initials: F
authors.lastname: Khan
authors.affiliation: Molecular Bioprospection Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Mahendra P
authors.initials: MP
authors.lastname: Darokar
authors.affiliation: Medicinal Chemistry Department, CSIR-Central Institute of Medicinal and Aromatic Plants, Lucknow, 226015, India.
authors.forename: Santosh Kumar
authors.initials: SK
authors.lastname: Srivastava
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology; D055808:Drug Discovery; D024901:Drug Resistance, Multiple, Bacterial; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D009268:Nalidixic Acid / Q000737:chemistry / Q000494:pharmacology*; D013752:Tetracycline / Q000494:pharmacology; D014315:Triterpenes / Q000737:chemistry / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D000251:Adenosine Triphosphatases; D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D009268:Nalidixic Acid; D013752:Tetracycline; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: ester analog; multidrug-resistant; nalidixic acid; non-antibiotics; tetracycline; triterpenoids