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

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

机构地区：[1]Hainan Affiliated Hospital of Hainan Medical University,Hainan General Hospital,Haikou,China [2]Center for Translational Research,Shenzhen Bay Laboratory,Shenzhen China [3]Key Laboratory of Tropical Biological Resources of Ministry of Education,School of Pharmaceutical Sciences,Hainan University,Haikou,China [4]Hainan Branch,Shanghai Children's Medical Center,School of Medicine,Shanghai Jiao Tong University,Sanya,China

出　　处：《mLife》2024年第3期445-458,共14页微生物（英文）

基　　金：This work was supported by the National Natural Science Foundation of China(Nos.82160664 and 31760246);the Hainan Province Science and Technology Special Fund(ZDYF2024SHFZ103);the Natural Science Foundation of Hainan Province(222RC557 and 221QN170);Anhui Laboratory of Molecule-Based Materials(fzj21006).

摘　　要：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 33β-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 newβ-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(50μg/ml)not only enhanced the susceptibility of the formed biofilms but also disrupted the architecture of biofilms by 84%.m-NPe(50μg/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,Rhll,RhiR,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(QSl)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 Qsl and antibiofilm agent capable of restoring or improving antimicrobial drug sensitivity.

关 键 词：biofilms quorum sensing Serratia marcescens virulence factors (E)-1-methyl-4-(2-nitrovinyl)benzene 

分 类 号：Q93[生物学—微生物学]