Collalto Diletta, Giallonardi Giulia, Fortuna Alessandra, Meneghini Carlo, Fiscarelli Ersilia, Visca Paolo, Imperi Francesco, Rampioni Giordano, Leoni Livia
Department of Science, Roma Tre University, Rome, Italy.
Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom.
Front Microbiol. 2022 Apr 25;13:845231. doi: 10.3389/fmicb.2022.845231. eCollection 2022.
The chronic lung infection caused by is a major cause of morbidity and mortality in cystic fibrosis (CF) patients. Antivirulence drugs targeting quorum sensing (QS) systems are intensively studied as antibiotics substitutes or adjuvants. Previous studies, carried out in non-CF reference strains, showed that the old drugs niclosamide and clofoctol could be successfully repurposed as antivirulence drugs targeting the and QS systems, respectively. However, frequent emergence of QS-defective mutants in the CF lung undermines the use of QS inhibitors in CF therapy. Here, QS signal production and susceptibility to niclosamide and clofoctol have been investigated in 100 CF isolates, with the aim of broadening current knowledge on the potential of anti-QS compounds in CF therapy. Results showed that 85, 78, and 69% of the CF isolates from our collection were proficient for the , , and QS systems, respectively. The ability of both niclosamide and clofoctol to inhibit QS and virulence was highly variable and strain-dependent. Niclosamide showed an overall low range of activity and its negative effect on signal production did not correlate with a decreased production of virulence factors. On the other hand, clofoctol displayed a broader QS inhibitory effect in CF isolates, with consequent reduction of the -controlled virulence factor pyocyanin. Overall, this study highlights the importance of testing new antivirulence drugs against large panels of CF clinical isolates before proceeding to further pre-clinical studies and corroborates previous evidence that strains naturally resistant to QS inhibitors occur among CF isolates. However, it is also shown that resistance to inhibitors is less frequent than resistance to inhibitors, thus supporting the development of inhibitors for antivirulence therapy in CF.
由[病原体名称未给出]引起的慢性肺部感染是囊性纤维化（CF）患者发病和死亡的主要原因。靶向[病原体名称未给出]群体感应（QS）系统的抗毒力药物作为抗生素替代品或佐剂正在深入研究中。先前在非CF[病原体名称未给出]参考菌株中进行的研究表明，老药氯硝柳胺和氯氟octol可分别成功重新用作靶向[病原体名称未给出]和[另一病原体名称未给出]QS系统的抗毒力药物。然而，CF肺部中QS缺陷突变体的频繁出现削弱了QS抑制剂在CF治疗中的应用。在此，对100株CF[病原体名称未给出]分离株的QS信号产生以及对氯硝柳胺和氯氟octol的敏感性进行了研究，目的是拓宽当前关于抗QS化合物在CF治疗中潜力的认识。结果表明，我们收集的CF分离株中分别有85%、78%和69%对[第一个QS系统名称未给出]、[第二个QS系统名称未给出]和[第三个QS系统名称未给出]QS系统功能正常。氯硝柳胺和氯氟octol抑制QS和毒力的能力高度可变且因菌株而异。氯硝柳胺显示出总体较低的活性范围，其对[第一个QS系统名称未给出]信号产生的负面影响与毒力因子产生的减少无关。另一方面，氯氟octol在CF分离株中表现出更广泛的QS抑制作用，从而降低了由[病原体名称未给出]控制的毒力因子绿脓菌素的产生。总体而言，本研究强调了在进行进一步的临床前研究之前，针对大量CF临床分离株测试新的抗毒力药物的重要性，并证实了先前的证据，即CF分离株中存在对QS抑制剂天然耐药的菌株。然而，研究还表明，对[病原体名称未给出]抑制剂的耐药性比对[另一病原体名称未给出]抑制剂的耐药性少见，因此支持开发用于CF抗毒力治疗的[病原体名称未给出]抑制剂。
