Discovery of β-nitrostyrene derivatives as potential quorum sensing inhibitors for biofilm inhibition and antivirulence factor therapeutics against <i>Serratia marcescens</i>

Jiang Wang; Jingyi Yang; Pradeepraj Durairaj; Wei Wang; Dongyan Wei; Shi Tang; Haiqing Liu; Dayong Wang; Ai-Qun Jia

doi:10.1002/mlf2.12135

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Original Research | Open Access

Discovery of β-nitrostyrene derivatives as potential quorum sensing inhibitors for biofilm inhibition and antivirulence factor therapeutics against Serratia marcescens

Jiang Wang^{¹^,²^,³^,^#}, Jingyi Yang^{³^,⁴^,^#}, Pradeepraj Durairaj^{²^,^a}, Wei Wang^³, Dongyan Wei^³, Shi Tang^³(), Haiqing Liu^³, Dayong Wang^³

(), Ai-Qun Jia^{¹^,³}

()

Hainan Affiliated Hospital of Hainan Medical University, Hainan General Hospital, Haikou, China

Center for Translational Research, Shenzhen Bay Laboratory, Shenzhen, China

Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou, China

Hainan Branch, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Sanya, China

^#Jiang Wang and Jing‐Yi Yang contributed equally to this study.

Present Address: ^aNational High Magnetic Field Laboratory, FAMU‐FSU College of Engineering, Florida State University, Tallahassee, Florida, USA.

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Abstract

Quorum sensing (QS) inhibition has emerged as a promising target for directed drug design, providing an appealing strategy for developing antimicrobials, particularly against infections caused by drug-resistant pathogens. In this study, we designed and synthesized a total of 33 β-nitrostyrene derivatives using 1-nitro-2-phenylethane (NPe) as the lead compound, to target the facultative anaerobic bacterial pathogen Serratia marcescens. The QS-inhibitory effects of these compounds were evaluated using S. marcescens NJ01 and the reporter strain Chromobacterium violaceum CV026. Among the 33 new β-nitrostyrene derivatives, (E)-1-methyl-4-(2-nitrovinyl)benzene (m-NPe, compound 28) was proven to be a potent inhibitor that reduced biofilm formation of S. marcescens NJ01 by 79%. Scanning electron microscopy (SEM) and confocal laser scanning microscopy (CLSM) results revealed that treatment with m-NPe (50 μg/ml) not only enhanced the susceptibility of the formed biofilms but also disrupted the architecture of biofilms by 84%. m-NPe (50 μg/ml) decreased virulence factors in S. marcescens NJ01, reducing the activity of protease, prodigiosin, and extracellular polysaccharide (EPS) by 36%, 72%, and 52%, respectively. In S. marcescens 4547, the activities of hemolysin and EPS were reduced by 28% and 40%, respectively, outperforming the positive control, vanillic acid (VAN). The study also found that the expression levels of QS- and biofilm-related genes (flhD, fimA, fimC, sodB, bsmB, pigA, pigC, and shlA) were downregulated by 1.21- to 2.32-fold. Molecular dynamics analysis showed that m-NPe could bind stably to SmaR, RhlI, RhlR, LasR, and CviR proteins in a 0.1 M sodium chloride solution. Importantly, a microscale thermophoresis (MST) test revealed that SmaR could be a target protein for the screening of a quorum sensing inhibitor (QSI) against S. marcescens. Overall, this study highlights the efficacy of m-NPe in suppressing the virulence factors of S. marcescens, identifying it as a new potential QSI and antibiofilm agent capable of restoring or improving antimicrobial drug sensitivity.

Keywords

biofilms quorum sensing Serratia marcescensvirulence factors (E)-1-methyl-4-(2-nitrovinyl)benzene

References

Miethke M, Pieroni M, Weber T, Brönstrup M, Hammann P, Halby L, et al. Towards the sustainable discovery and development of new antibiotics. Nat Rev Chem. 2021;5:726–49.