Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa.
Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa.
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DOI：
10.1371/journal.ppat.1000883
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发表时间：
2010-05-06
期刊：
影响因子：
6.7
通讯作者：
van Delden C
中科院分区：
文献类型：
--
作者：
Köhler T;Perron GG;Buckling A;van Delden C
随着细菌耐药性的不断发展，寻找传统抗菌药物以外的新药物已成为公共卫生研究的一个关键目标。可能的创新策略包括抑制细菌毒力。然而，必须考虑到这种新干预措施的演变和环境后果。铜绿假单胞菌的毒力和合作社会行为依赖于群体感应（QS）控制的胞外产物（公共产品）的生产。因此，QS是抗毒力干预的有吸引力的靶标。在定殖过程中，受益于野生型分离株提供的公共产品的非合作（并且因此毒性较低）铜绿假单胞菌QS突变体自然地增加频率，从而提供相对保护免受侵入性感染。我们假设抑制QS介导的基因表达消除了这种生长优势和选择毒性较低的QS突变体，并保持了毒性更强的QS野生型细菌的优势。我们在一项安慰剂对照试验中探讨了这种可能性，该试验研究了阿奇霉素的抗QS特性，阿奇霉素是一种大环内酯类抗生素，对铜绿假单胞菌没有杀菌活性，但在铜绿假单胞菌定植的插管患者中干扰QS。在不存在阿奇霉素的情况下，非合作（因此毒性较低）lasR（QS）突变体的频率随时间增加。阿奇霉素显着降低QS-基因表达直接测量气管吸出物。同时，lasR突变体的优势丧失，并且在阿奇霉素治疗期间，毒性野生型分离株占主导地位。我们证实了这些结果在体外与健身和入侵实验。阿奇霉素降低野生型的生长速率，但不是lasR突变体。此外，lasR-突变体有效地侵入野生型种群的情况下，但不是在阿奇霉素的存在下。这些体内和体外结果表明，基于QS阻断的抗毒力干预措施减少了对降低毒力的自然选择，因此可能会增加医院环境中更具毒力基因型的患病率。更一般地说，应评估干预措施对致病菌毒力演变的影响。 ClinicalTrials.gov随着抗生素耐药性的不断发展和医院内病原体的快速传播，寻找传统抗生素以外的新治疗方法成为公共卫生研究的关键目标。因此，抗毒力疗法可能是替代的抗菌策略。然而，必须考虑到这种干预可能造成的演变和环境后果。在这里，我们展示了一个显着的抗毒力干预的进化影响。铜绿假单胞菌的毒力和合作社会行为依赖于群体感应（QS）控制的胞外产物的产生。在缺乏特异性干预的情况下，不合作（因此毒性较低）的QS突变体利用并受益于野生型分离株提供的产物。因此，这些毒性较低的突变体的频率增加，并提供了相对的保护免受感染的殖民患者。相比之下，当QS-基因表达减少的QS-抑制药物阿奇霉素，这一优势的QS-突变体是丢失和强毒菌株占主导地位，无论是在定殖患者和在体外实验。这些结果表明，在医院环境中，QS阻断可能会增加定植分离株中毒性更强的QS应答者的患病率。更一般地说，需要评估抗病力干预措施对病原菌的生态和毒力演变的影响。
With the rising development of bacterial resistance the search for new medical treatments beyond conventional antimicrobials has become a key aim of public health research. Possible innovative strategies include the inhibition of bacterial virulence. However, consideration must be given to the evolutionary and environmental consequences of such new interventions. Virulence and cooperative social behaviour of the bacterium Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products (public goods). Hence QS is an attractive target for anti-virulence interventions. During colonization, non-cooperating (and hence less virulent) P. aeruginosa QS-mutants, benefiting from public goods provided by wild type isolates, naturally increase in frequency providing a relative protection from invasive infection. We hypothesized that inhibition of QS-mediated gene expression removes this growth advantage and selection of less virulent QS-mutants, and maintains the predominance of more virulent QS-wild type bacteria. We addressed this possibility in a placebo-controlled trial investigating the anti-QS properties of azithromycin, a macrolide antibiotic devoid of bactericidal activity on P. aeruginosa, but interfering with QS, in intubated patients colonized by P. aeruginosa. In the absence of azithromycin, non-cooperating (and hence less virulent) lasR (QS)-mutants increased in frequency over time. Azithromycin significantly reduced QS-gene expression measured directly in tracheal aspirates. Concomitantly the advantage of lasR-mutants was lost and virulent wild-type isolates predominated during azithromycin treatment. We confirmed these results in vitro with fitness and invasion experiments. Azithromycin reduced growth rate of the wild-type, but not of the lasR-mutant. Furthermore, the lasR-mutant efficiently invaded wild-type populations in the absence, but not in the presence of azithromycin. These in vivo and in vitro results demonstrate that anti-virulence interventions based on QS-blockade diminish natural selection towards reduced virulence and therefore may increase the prevalence of more virulent genotypes in the Hospital environment. More generally, the impact of intervention on the evolution of virulence of pathogenic bacteria should be assessed. Trial Registration: ClinicalTrials.gov NCT00610623 With the rising development of antibiotic resistance and rapid spread of nosocomial pathogens, the search for new treatments beyond conventional antibiotics becomes a key aim of public health research. As such, anti-virulence therapies might be alternative antimicrobial strategies. However, consideration must be given to the potential evolutionary and environmental consequences of such interventions. Here we demonstrate a significant evolutionary impact of an anti-virulence intervention. Virulence and cooperative social behaviour of Pseudomonas aeruginosa rely on the quorum-sensing (QS) controlled production of extracellular products. In the absence of a specific intervention, non-cooperating (and hence less virulent) QS-mutants exploit and benefit from products provided by wild type isolates. As a consequence these less virulent mutants increase in frequency and provide a relative protection against infection to a colonized patient. In contrast, when QS-gene expression is reduced by the QS-inhibiting drug azithromycin, this advantage of QS-mutants is lost and virulent isolates predominate both in colonized patients and during in vitro experiments. These results suggest that QS-blockade may increase the prevalence of more virulent QS-responders among colonizing isolates in the hospital environment. More generally, the impact of anti-virulence interventions on the ecology and evolution of virulence of pathogenic bacteria needs to be assessed.
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影响因子：
2.9
作者：
LENSKI, RE;ROSE, MR;TADLER, SC
通讯作者：
TADLER, SC
影响因子：
3.2
作者：
Pearson, JP;Pesci, EC;Iglewski, BH
通讯作者：
Iglewski, BH
DOI：
10.1098/rspb.2002.2209
发表时间：
2003-01-07
影响因子：
4.7
作者：
West, SA;Buckling, A
通讯作者：
Buckling, A
影响因子：
11.8
作者：
通讯作者：
--
影响因子：
4.9
作者：
Nalca, Y;Jänsch, L;Hussler, S
通讯作者：
Hussler, S