Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound

The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12–0.5 μg/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome

Inspiration from old dyes: Tris(stilbene) compounds as potent gram-positive antibacterial agents

Herein we describe the preparation and structure-activity relationship studies on range of stilbene based compounds and their antibacterial activity. Two related compounds, each bearing carboxylic acid moieties, exhibit good activity against several bacterial strains, including methicillin-resistant Staphylococcus aureus MRSA (ATCC 33592 and NCTC 10442). Compound 10 was most active against Moraxella catarrhalis with minimum inhibitory concentrations (MICs) of 0.12-0.25 μg mL-1 and against Staphylococcus spp. with MICs ranging from 2-4 μg mL-1. The derivative 17 showed increased activity with MICs of 0.06-0.25 μg mL-1 against M. catarrhalis and 0.12-1 against Staphylococcus spp. This level of activity is similar to that reported for S. aureus for antibiotics, such as vancomycin, with MICs of ≤2.0 μg mL-1 and clindamycin with MICs of ≤0.5 μg mL -1. As an indicator of toxicity, 17 was tested for its ability to lyse sheep erythrocytes, and showed low haemolytic activity. Such results highlight the value of tris(stilbene) compounds as antibacterial agents providing suitable properties for further development. Routes to new antibiotics: The preparation of and structure-activity relationship studies on a range of stilbene based compounds revealed two related compounds, each bearing carboxylic acid moieties, exhibiting pronounced activity against several bacterial strains including methicillin-resistant Staphylococcus aureus, MRSA (see scheme, dba = dibenzylidene acetone)