Synergy Potential of Indole Alkaloids and Its Derivative against Drug‐resistant Escherichia coli. (21st August 2015)

• Record Type: Journal Article
• Authors: Dwivedi, Gaurav Raj; Gupta, Shikha; Maurya, Anupam; Tripathi, Shubhandra; Sharma, Ashok; Darokar, Mahendra P.; Srivastava, Santosh K.
• Is Part Of: Chemical biology & drug design. Volume 86:Number 6(2015:Dec.)
• Page Start: 1471
• Page End: 1481
• Publication Date: 2015-08-21
• Subjects: antibacterial combination -- indole alkaloids -- MDREC -- nalidixic acid -- semisynthetic derivatives -- tetracycline; Drugs -- Design -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; 615.19005
• DOI: 10.1111/cbdd.12613
• Languages: English
• ISSNs: 1747-0277

Abstract

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 DH5 α were also evaluated. The IA1, 2, 4, 5, 9 and the derivative9F showed eightfold reduction in the MIC of NAL against the DH5 α 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. Abstract : Synergy potential of the indole alkaloids, 1, 2, 4, 5, 9 and a semi‐synthetic derivative 9F was deduced by inhibiting efflux pumps and down‐regulation of the efflux pump genes. The in silico ADME analysis revealed that some of these alkaloids 1 and 9 are safe, nontoxic and possess good intestinal absorption, which makes them suitable leads for further drug development.