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

Nikki Y T Man,Scott G Stewart,Allan J Mckinley,Thomas V Riley,Katherine A Hammer,Daniel R Knight

doi:10.1038/s41598-018-25080-w

Abstract

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.

Highlights

Antimicrobial resistance (AMR) is one of the most problematic public health issues that society faces today
Susceptibility testing of a range of aerobic bacterial species showed that compound
135C was active against Gram-positive bacteria and active against the Gram negative species Moraxella catarrhalis (Table 1)

Summary

Introduction

Antimicrobial resistance (AMR) is one of the most problematic public health issues that society faces today. A previous study of a promising antibacterial stilbene compound found in silico led to triacid derivative 135C (Fig. 1) In this previous medicinal chemistry study, 135C was found to exhibit antibacterial activity[13] against several Gram-positive bacteria in vitro, including methicillin-resistant Staphylococcus aureus (MRSA), at concentrations comparable to those required for existing antibiotics[14]. Other natural stilbenes with antibacterial activity, such as resveratrol[15], have been studied in detail but none contain this tri-styrene motif Given that this compound falls outside any known existing antibacterial classes, the benefits from developing it as a potential antibacterial agent are considerable, as there may be a reduced likelihood of observing antibacterial cross-resistance[16] and it is possible that the compound has a novel mode of antibacterial action. A genomic comparison of the resultant 135C-resistant mutant strains and wildtype parent strains was performed

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Conclusion