Evidence for Complex Interplay between Quorum Sensing and Antibiotic Resistance in Pseudomonas aeruginosa.
Evidence for Complex Interplay between Quorum Sensing and Antibiotic Resistance in Pseudomonas aeruginosa.
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DOI：
10.1128/spectrum.01269-22
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发表时间：
2022-12-21
影响因子：
3.7
通讯作者：
Elias, Mikael H.
中科院分区：
文献类型：
--
作者：
Sikdar, Rakesh;Elias, Mikael H.
群体感应(Quorum Sensing，QS)是一种依赖于细胞密度的、由可扩散的小信号分子介导的细胞间通讯系统。QS调节一系列细菌行为，包括生物膜形成、毒力、耐药机制和抗生素耐受性。能够降解信号分子的酶可以干扰QS-这一过程被称为群体猝灭(QQ)。值得注意的是，以前的工作报道了一些QS中的酶干扰与抗生素对铜绿假单胞菌的协同作用。联合治疗的前提对对抗耐多药细菌很有吸引力，但缺乏全面的研究。在这里，我们通过测试来自15个不同类别的222种抗生素和抗菌化合物来评估QS信号中断对铜绿假单胞菌耐药性的影响。我们发现令人信服的证据表明，QS信号中断确实影响了抗生素耐药性(40%的被测试化合物；/222)，尽管并不总是协同作用(19%的化合物不协同；43/222)。对于一些被测试的抗生素，如磺胺噻唑和甲氧苄啶，我们能够将QS信号中断引起的耐药性变化与叶酸生物合成途径关键基因的表达调控联系起来。此外，利用基于铜绿假单胞菌的线虫致死模型，我们在体内证实了酶QQ调节抗生素对铜绿假单胞菌致病性的影响。综上所述，这些结果表明，信号干扰对铜绿假单胞菌的耐药谱有深刻而复杂的影响。这项工作表明，包括QQ和抗生素在内的联合疗法不应该在全球范围内讨论，而应该在个案研究中讨论。重要性群体感应(QS)是一种依赖细胞密度的通讯系统，被广泛的细菌用来协调行为。与QS相关的干扰策略是控制依赖QS的微生物行为的吸引人的方法，包括毒力和生物被膜。此前有报道称，对QS的干预与抗生素有协同作用，但尚不存在系统性评估。在这里，我们评估了使用模型条件人类病原体铜绿假单胞菌PA14进行联合治疗的可能性。在这个模型中，收集的数据表明，QS在很大程度上调节了PA14的抗生素耐药性(对40%以上的测试药物)。然而，联合治疗的结果只有19%是协同的。这项研究证明了QS与抗生素耐药性之间的复杂关系，并建议包括QS抑制剂和抗生素在内的联合治疗不应进行全局性讨论，而应进行个案研究。
Quorum sensing (QS) is a cell-density-dependent, intercellular communication system mediated by small diffusible signaling molecules. QS regulates a range of bacterial behaviors, including biofilm formation, virulence, drug resistance mechanisms, and antibiotic tolerance. Enzymes capable of degrading signaling molecules can interfere in QS—a process termed as quorum quenching (QQ). Remarkably, previous work reported some cases where enzymatic interference in QS was synergistic to antibiotics against Pseudomonas aeruginosa. The premise of combination therapy is attractive to fight against multidrug-resistant bacteria, yet comprehensive studies are lacking. Here, we evaluate the effects of QS signal disruption on the antibiotic resistance profile of P. aeruginosa by testing 222 antibiotics and antibacterial compounds from 15 different classes. We found compelling evidence that QS signal disruption does indeed affect antibiotic resistance (40% of all tested compounds; 89/222), albeit not always synergistically (not synergistic for 19% of compounds; 43/222). For some tested antibiotics, such as sulfathiazole and trimethoprim, we were able to relate the changes in resistance caused by QS signal disruption to the modulation of the expression of key genes of the folate biosynthetic pathway. Moreover, using a P. aeruginosa-based Caenorhabditis elegans killing model, we confirmed that enzymatic QQ modulates the effects of antibiotics on P. aeruginosa’s pathogenicity in vivo. Altogether, these results show that signal disruption has profound and complex effects on the antibiotic resistance profile of P. aeruginosa. This work suggests that combination therapy including QQ and antibiotics should be discussed not globally but, rather, in case-by-case studies. IMPORTANCE Quorum sensing (QS) is a cell-density-dependent communication system used by a wide range of bacteria to coordinate behaviors. Strategies pertaining to the interference in QS are appealing approaches to control microbial behaviors that depend on QS, including virulence and biofilms. Interference in QS was previously reported to be synergistic with antibiotics, yet no systematic assessment exists. Here, we evaluate the potential of combination treatments using the model opportunistic human pathogen Pseudomonas aeruginosa PA14. In this model, collected data demonstrate that QS largely modulates the antibiotic resistance profile of PA14 (for more than 40% of the tested drugs). However, the outcome of combination treatments is synergistic for only 19% of them. This research demonstrates the complex relationship between QS and antibiotic resistance and suggests that combination therapy including QS inhibitors and antibiotics should be discussed not globally but, rather, in case-by-case studies.
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DOI：
10.3390/antibiotics3010001
发表时间：
2014-01-21
期刊：
Antibiotics (Basel, Switzerland)
影响因子：
--
作者：
Bourne CR
通讯作者：
Bourne CR
影响因子：
4.6
作者：
Bergonzi C;Schwab M;Naik T;Daudé D;Chabrière E;Elias M
通讯作者：
Elias M
影响因子：
16.6
作者：
Chua, Song Lin;Liu, Yang;Yang, Liang
通讯作者：
Yang, Liang
DOI：
10.1016/j.ijantimicag.2016.06.023
发表时间：
2016-12-01
影响因子：
10.8
作者：
Baron, Sophie;Hadjadj, Linda;Olaitan, Abiola Olumuyiwa
通讯作者：
Olaitan, Abiola Olumuyiwa
影响因子：
3.9
作者：
Aslam B;Wang W;Arshad MI;Khurshid M;Muzammil S;Rasool MH;Nisar MA;Alvi RF;Aslam MA;Qamar MU;Salamat MKF;Baloch Z
通讯作者：
Baloch Z