Schaadt Nadine S, Steinbach Anke, Hartmann Rolf W, Helms Volkhard
Center for Bioinformatics, Saarland University, Campus E2,1, 66123 Saarbrücken, Germany.
BMC Syst Biol. 2013 Aug 21;7:81. doi: 10.1186/1752-0509-7-81.
In the pathogen P. aeruginosa, the formation of virulence factors is regulated via Quorum sensing signaling pathways. Due to the increasing number of strains that are resistant to antibiotics, there is a high interest to develop novel antiinfectives. In the combat of resistant bacteria, selective blockade of the bacterial cell-to-cell communication (Quorum sensing) has gained special interest as anti-virulence strategy. Here, we modeled the las, rhl, and pqs Quorum sensing systems by a multi-level logical approach to analyze how enzyme inhibitors and receptor antagonists effect the formation of autoinducers and virulence factors.
Our rule-based simulations fulfill the behavior expected from literature considering the external level of autoinducers. In the presence of PqsBCD inhibitors, the external HHQ and PQS levels are indeed clearly reduced. The magnitude of this effect strongly depends on the inhibition level. However, it seems that the pyocyanin pathway is incomplete.
To match experimental observations we suggest a modified network topology in which PqsE and PqsR acts as receptors and an autoinducer as ligand that up-regulate pyocyanin in a concerted manner. While the PQS biosynthesis is more appropriate as target to inhibit the HHQ and PQS formation, blocking the receptor PqsR that regulates the biosynthesis reduces the pyocyanin level stronger.
在病原菌铜绿假单胞菌中，毒力因子的形成是通过群体感应信号通路调控的。由于对抗生素耐药的菌株数量不断增加，人们对开发新型抗感染药物有着浓厚的兴趣。在对抗耐药细菌的过程中，作为一种抗毒力策略，选择性阻断细菌细胞间通讯（群体感应）受到了特别关注。在此，我们采用多层次逻辑方法对las、rhl和pqs群体感应系统进行建模，以分析酶抑制剂和受体拮抗剂如何影响自诱导物和毒力因子的形成。
我们基于规则的模拟符合从文献中预期的考虑自诱导物外部水平的行为。在存在PqsBCD抑制剂的情况下，外部HHQ和PQS水平确实明显降低。这种效应的大小强烈取决于抑制水平。然而，似乎绿脓菌素途径是不完整的。
为了与实验观察结果相匹配，我们提出了一种修改后的网络拓扑结构，其中PqsE和PqsR作为受体，一种自诱导物作为配体，协同上调绿脓菌素。虽然PQS生物合成作为抑制HHQ和PQS形成的靶点更为合适，但阻断调节生物合成的受体PqsR会更强地降低绿脓菌素水平。
