Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa,ACS Infectious Diseases

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Binding Mode Characterization and Early in Vivo Evaluation of Fragment-Like Thiols as Inhibitors of the Virulence Factor LasB from Pseudomonas aeruginosa
ACS Infectious Diseases ( IF 4.0 ) Pub Date : 2018-02-27 00:00:00 , DOI: 10.1021/acsinfecdis.8b00010
Andreas M. Kany ₁ , Asfandyar Sikandar ₂ , Jörg Haupenthal ₁ , Samir Yahiaoui ₁ , Christine K. Maurer ₁ , Ewgenij Proschak ₃ , Jesko Köhnke ₂ , Rolf W. Hartmann _{1,

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Affiliation

The increasing emergence of antibiotic resistance necessitates the development of anti-infectives with novel modes of action. Targeting bacterial virulence is considered a promising approach to develop novel antibiotics with reduced selection pressure. The extracellular collagenase elastase (LasB) plays a pivotal role in the infection process of Pseudomonas aeruginosa and therefore represents an attractive antivirulence target. Mercaptoacetamide-based thiols have been reported to inhibit LasB as well as collagenases from clostridia and bacillus species. The present work provides an insight into the structure–activity relationship (SAR) of these fragment-like LasB inhibitors, demonstrating an inverse activity profile compared to similar inhibitors of clostridial collagenase H (ColH). An X-ray cocrystal structure is presented, revealing distinct binding of two compounds to the active site of LasB, which unexpectedly maintains an open conformation. We further demonstrate in vivo efficacy in a Galleria mellonella infection model and high selectivity of the LasB inhibitors toward human matrix metalloproteinases (MMPs).

中文翻译：

铜绿假单胞菌毒力因子LasB的片段样硫醇的结合模式表征和体内早期评价。

越来越多的抗生素耐药性的出现使得必须开发具有新作用方式的抗感染药。靶向细菌毒力被认为是开发具有降低选择压力的新型抗生素的有前途的方法。细胞外胶原酶弹性蛋白酶（LasB）在铜绿假单胞菌的感染过程中起关键作用因此代表了有吸引力的抗毒目标。据报道，基于巯基乙酰胺的硫醇抑制LasB以及梭状芽胞杆菌和芽孢杆菌属的胶原酶。本工作提供了对这些片段状LasB抑制剂的结构-活性关系（SAR）的见解，与梭状胶原酶H（ColH）的类似抑制剂相比，具有相反的活性。呈现了X射线共晶体结构，揭示了两种化合物与LasB活性位点的独特结合，这出乎意料地保持了开放构象。我们进一步证明体内功效在蜡螟感染对人基质金属蛋白酶（MMP）的抑制剂LasB的模型和高选择性。

更新日期：2018-02-27

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