Abstract
Disulfides from Allium stipitatum, commonly known as Persian shallot, were previously reported to possess antibacterial properties. Analogues of these compounds, produced by S-methylthiolation of appropriate thiols using S-methyl methanethiosulfonate, exhibited antimicrobial activity, with one compound inhibiting the growth of Mycobacterium tuberculosis at 17 µM (4 mg L−1) and other compounds inhibiting Escherichia coli and multi-drug-resistant (MDR) Staphylococcus aureus at concentrations ranging between 32–138 µM (8–32 mg L−1). These compounds also displayed moderate inhibitory effects on Klebsiella and Proteus species. Whole-cell phenotypic bioassays such as the spot-culture growth inhibition assay (SPOTi), drug efflux inhibition, biofilm inhibition and cytotoxicity assays were used to evaluate these compounds. Of particular note was their ability to inhibit mycobacterial drug efflux and biofilm formation, while maintaining a high selectivity towards M. tuberculosis H37Rv. These results suggest that methyl disulfides are novel scaffolds which could lead to the development of new drugs against tuberculosis (TB).
Highlights
Given the continuing issues of multidrug-resistant (MDR) and extensively-drug-resistant (XDR) cases that are increasingly associated with clinically-relevant Gram-positive, Gram-negative and acid-fast human pathogens, there is a pressing need to develop new classes of antibacterials[3,4,5]
The spot culture growth inhibition (SPOTi) assay is a whole-cell phenotypic screen that is routinely used to identify novel antimicrobial molecules with clinical relevance[12,13]. This rapid but gold-standard assay was applied to evaluate the antimicrobial activity of the synthesized compounds against Gram-positive, Gram-negative and acid-fast bacteria
Based on the encouraging results when tested against the non-pathogenic model of M. tuberculosis organisms, M. aurum (ATCC23366) and M. bovis BCG (ATCC35734), the compounds were subsequently tested against M. tuberculosis H37Rv and its multidrug-resistant clinical isolates (Mtb-MDR1 and Mtb-MDR2)
Summary
Given the continuing issues of multidrug-resistant (MDR) and extensively-drug-resistant (XDR) cases that are increasingly associated with clinically-relevant Gram-positive, Gram-negative and acid-fast human pathogens (such as Staphylococcus aureus, Escherichia coli and Mycobacterium tuberculosis respectively), there is a pressing need to develop new classes of antibacterials[3,4,5]. Paradigm, efflux pump-related multidrug-resistance significantly contributes to a reduction in drug accumulation and often renders antibiotics redundant[7]. This could be circumvented by molecules that interfere with or inhibit antibiotic efflux[8,9]. Multidrug efflux pumps are often transmembrane proteins that secrete metabolites involved in quorum-sensing[10]. This cross-talk between bacteria is believed to be essential for the formation and dispersion of bacterial biofilms[11]. Inhibition of multidrug efflux pumps is a strategy to inhibit biofilm formation, which is a major contributor to antimicrobial resistance[11]. The aim of this study was to synthesise the novel disulphide compounds mentioned earlier and comprehensively evaluate their biological activity to optimise the chemical scaffold as a prospective therapeutic lead
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