Inhibition of Pseudomonas aeruginosa quorum sensing by AI-2 analogs

Autoinducer-2 (AI-2) has been suggested to serve as a universal interspecies quorum sensing signaling molecule. We have synthesized a set of AI-2 analogs with small incremental changes in alkyl substitution on C-2 and evaluated them for their agonistic and antagonistic potential as quorum sensing (QS) attenuators in two different bacterial species: Pseudomonas aeruginosa and Vibrio harveyi. Unexpectedly, several of the analogs were found to function as synergistic QS agonists in V. harveyi, while two of these analogs inhibit QS in P. aeruginosa.     

Screening and anti-virulent study of N-acyl homoserine lactones DNA aptamers against Pseudomonas aeruginosa quorum sensing

In Pseudomonas aeruginosa, a quorum sensing (QS) system regulates the expression of many virulence factors. N-acyl homoserine lactone (HSL) is the signal molecule of QS system. In order to find a novel HSL binder to interfere with QS signaling and to attenuate P. aeruginosa virulence, an amino lactam surrogate (ALS) of HSL was used as a target to screen HSL aptamers with the technique of systematic evolution of ligands by exponential enrichment (SELEX). Eight HSL aptamers with high affinities for 3O-C12-HSL (20 nM ≤ K _d < 35 nM) or C4-HSL (25 nM < K _d < 50 nM) were finally obtained. In vitro QS-inhibiting study of P. aeruginosa showed that HSL aptamers could inhibit virulence in a dose-dependent manner. ALSap-8 which bound C4-HSL primarily acted on the rhl system and inhibited the secretion of pyocyanin. ALSap-5 which bound 3O-C12-HSL not only showed strong inhibitory activity on biofilm formation as well as secretions of LasA protease and LasB elastase, but also reduced pyocyanin secretion. Since the las system is capable of activating the rhl system mildly, we speculated that ALSap-5 can simultaneously interfere with the las and rhl systems. High-affinity aptamers against HSL in this study are novel QS and virulence-inhibitors, and may have potential as drug candidates for the treatment of P. aeruginosa infection.     

群体感应对铜绿假单胞菌生物被膜形成的调控

生物被膜是一种与浮游细胞相对应的生长方式,由细菌和自身分泌的包外基质组成。铜绿假单胞菌是研究这一生长方式的模式生物。在过去十年,对铜绿假单胞菌生物被膜的研究已取得显著进展。群体感应(QS)的细胞沟通机制在铜绿假单胞菌生物被膜形成中发挥着重要作用。介绍生物被膜的特点,并重点讨论了QS和生物被膜之间的关系。     

铜绿假单胞菌群体感应抑制剂研究进展

铜绿假单胞菌是一种常见的机会致病菌,可在人群中引起严重的急性和慢性感染,是病人在医院期间发生感染的第三大致病菌。铜绿假单胞菌多种毒力因子的分泌以及生物被膜的形成都是受一种被称为群体感应(Quorum Sensing,QS)的胞间信号传导系统调控的。QS使细菌能够根据细胞密度变化进行基因表达的调控。通过抑制QS来治疗铜绿假单胞菌感染是一个很有前景的发展方向。本文将就近年来铜绿假单胞菌群体感应抑制剂的研究进展进行综述。     

A mathematical model for quorum sensing in Pseudomonas aeruginosa

The bacteria Pseudomonas aeruginosa use the size and density of their colonies to regulate the production of a large variety of substances, including toxins. This phenomenon, called quorum sensing, apparently enables colonies to grow to sufficient size undetected by the immune system of the host organism. In this paper, we present a mathematical model of quorum sensing in P. aeruginosa that is based on the known biochemistry of regulation of the autoinducer that is crucial to this signalling mechanism. Using this model we show that quorum sensing works because of a biochemical switch between two stable steady solutions, one with low levels of autoinducer and one with high levels of autoinducer.     

A phage-encoded anti-activator inhibits quorum sensing in Pseudomonas aeruginosa

1. Download : Download high-res image (105KB)
2. Download : Download full-size image

     

Inhibition of biofilm formation, quorum sensing and infection in Pseudomonas aeruginosa by natural products-inspired organosulfur compounds

Using a microplate-based screening assay, the effects on Pseudomonas aeruginosa PAO1 biofilm formation of several S-substituted cysteine sulfoxides and their corresponding disulfide derivatives were evaluated. From our library of compounds, S-phenyl-L-cysteine sulfoxide and its breakdown product, diphenyl disulfide, significantly reduced the amount of biofilm formation by P. aeruginosa at levels equivalent to the active concentration of 4-nitropyridine-N-oxide (NPO) (1 mM). Unlike NPO, which is an established inhibitor of bacterial biofilms, our active compounds did not reduce planktonic cell growth and only affected biofilm formation. When used in a Drosophila-based infection model, both S-phenyl-L-cysteine sulfoxide and diphenyl disulfide significantly reduced the P. aeruginosa recovered 18 h post infection (relative to the control), and were non-lethal to the fly hosts. The possibility that the observed biofilm inhibitory effects were related to quorum sensing inhibition (QSI) was investigated using Escherichia coli-based reporters expressing P. aeruginosa lasR or rhIR response proteins, as well as an endogenous P. aeruginosa reporter from the lasI/lasR QS system. Inhibition of quorum sensing by S-phenyl-L-cysteine sulfoxide was observed in all of the reporter systems tested, whereas diphenyl disulfide did not exhibit QSI in either of the E. coli reporters, and showed very limited inhibition in the P. aeruginosa reporter. Since both compounds inhibit biofilm formation but do not show similar QSI activity, it is concluded that they may be functioning by different pathways. The hypothesis that biofilm inhibition by the two active compounds discovered in this work occurs through QSI is discussed.     

铜绿假单胞菌群体感应系统研究进展

群体感应系统是一种细胞密度依赖的基因表达系统,其广泛存在于细菌性病原体中,是细菌细胞通讯方式的一种。群体感应系统可利用细菌释放的信号分子不断监控周围细菌的密度。当细菌密度达到阈值时,群体感应系统网络将启动,参与调控生物被膜、细菌毒力等特定基因的表达,从而使临床抗感染治疗失败。而通过抑制群体感应系统,可一定程度上治疗铜绿假单胞菌引起的感染。本文通过查阅近年国内外相关文献,对铜绿假单胞菌群体感应系统研究进展进行总结,为临床铜绿假单胞菌治疗提供新的方向,即群体感应系统抑制剂有可能成为治疗铜绿假单胞菌感染的新策略。     

Modeling the quorum sensing regulatory network of human-pathogenic Pseudomonas aeruginosa

The biochemical network underlying quorum sensing in human-pathogenic Pseudomonas aeruginosa is one of the best characterized. Mathematical modeling is required to untangle the complexity of its architecture and dynamics. We present a qualitative model of the P. aeruginosa quorum-sensing network including interactions between the las and rhl modules, the signaling molecule PQS and the regulatory proteins Mvfr and VfR. Simulations exemplify the model to reproduce natural network behavior and suggest quorum-sensing responses to pharmacological interference.     

2-Methoxycyclopentyl analogues of a Pseudomonas aeruginosa quorum sensing modulator

Diastereomeric 2-methoxycyclopentyl analogues of a natural quorum sensing signaling molecule from Pseudomonas aeruginosa were synthesized and screened in pigment production assays with P. aeruginosa and Serratia strain ATCC39006.     

铜绿假单胞菌群体感应抑制物筛选系统的构建及其应用

针对调控铜绿假单胞菌致病基因表达的群体感应系统,将相关基因lasI和rhlA的启动子域与蔗糖致死基因相融合,构建出一个能通过菌体生长量来检测群体感应系统小分子抑制物的筛选体系。并在特定条件下,对一系列中药提取物进行筛选,同时用荧光筛选系统对结果进行验证。以此筛选出3种中药提取物对铜绿假单胞菌群体感应系统有不同程度的抑制作用。这3种中药分别隶属于爵床科、败酱科和萝藦科植物。本研究所构建的筛选体系能有效地筛选群体感应系统的抑制物,为进一步了解和控制细菌的致病感染过程和新药物的研究提供了一个有用的工具。