Evaluation of withaferin-A and analogues as antibacterial agents: Structure-activity relationship study

Infectious diseases are the second major cause of death, accounting for 57 million deaths each year worldwide. The plants play an important role in drug discovery and development that exhibit antimicrobial activities. Withania is a small genus which are distributed in the East of the Mediterranean area, Macaronesian region and extend to south Asia. The therapeutic potential of Withania species has been attributed to the presence of withanolides, which are a group of naturally occurring C28 steroids based on an ergostane skeleton [1]. While numerous studies on the anticancer properties of whitanolides were carried out, to our knowledge, slight research has been performed, about the antimicrobial properties and the determination of functional groups responsible for the activity. In view of the above, we evaluated the antimicrobial activity of fourteen withanolides from W. aristata and two derivative of withaferin-A (1). Seven of these withanolides exhibited antibacterial activity against sporulated bacteria, B. subtilis and B. cereus, with MIC values ranging from 40 to 1.2 µg/ml. Withaferin-A (1) 27-deoxi-withaferin A (2), and 27-O-(tert-butyldimethylsilyl)-4-dehydroxy-4-oxo-withaferin A (10), were also active against cocci bacteria. All compounds were inactive against Gram (-) bacteria and Candida albicans. The SAR study revealed valuable information on the role epoxide ring and the importance of the functional group at C-27, on the modulation of the activity. The killing curves showed that compound 2 was bactericide on B. cereus and B. subtilis cells, whereas bacteriostatic effect withanolides 1, 2 and 10 against S. aureus, S. saprophyticus and E. faecalis cells was observed. The macromolecular synthesis studies of 2 on S. aureus verified a cessation of all precursor incorporation but not simultaneously indicating a preferentially inhibition on some biosynthetic pathways. In fact, RNA and protein synthesis were stopped early.

Keywords: Whitanolides, Whitania aristata, antimicrobial activity, structure-activity relationship

References:

[1] Li-Xia Chen, Hao he, Fen Qiu. Natural withanolides: an overview. Nat. Prod. Rep., 2011, 28, 705.