Nutrient availability as a mechanism for selection of antibiotic tolerant Pseudomonas aeruginosa within the CF airway.
Nutrient availability as a mechanism for selection of antibiotic tolerant Pseudomonas aeruginosa within the CF airway.
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DOI：
10.1371/journal.ppat.1000712
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发表时间：
2010-01-08
期刊：
影响因子：
6.7
通讯作者：
Miller SI
中科院分区：
文献类型：
--
作者：
Hoffman LR;Richardson AR;Houston LS;Kulasekara HD;Martens-Habbena W;Klausen M;Burns JL;Stahl DA;Hassett DJ;Fang FC;Miller SI
微生物在宿主组织慢性感染期间受到选择性压力。在转录调节因子LasR中具有失活突变的铜绿假单胞菌分离株经常在囊性纤维化（CF）患者的气道内被选择，并且这些分离株的感染与较差的肺功能结果相关。lasR突变的潜在选择机制尚不清楚，但已被假定涉及CF气道分泌物中特定营养物质的丰度。我们表征了lasR突变铜绿假单胞菌菌株和分离株，以鉴定CF气道中发现的选择lasR突变体生长的条件。相对于野生型铜绿假单胞菌，lasR突变体表现出显著的代谢转变，包括降低的氧消耗和增加的硝酸盐利用，这被预测为在已知发生在CF气道中的营养条件下赋予增加的适应性。lasR突变体所表现出的这种代谢转变赋予了对CF护理中经常使用的两种抗生素妥布霉素和环丙沙星的抗性，即使在氧依赖性生长条件下也是如此，但体外对这些突变体的选择不需要预先暴露于抗生素。体内LasR功能丧失的选择以及相关的不良临床影响可能是由于缺氧和富含硝酸盐的CF气道中细菌生长增加以及由此产生的对治疗性抗生素的耐药性。不同慢性感染适应细菌之间的代谢相似性表明慢性感染期间的适应和抗生素耐药性的共同模式，其主要由响应于宿主组织内的营养可用性的细菌代谢变化驱动。慢性感染与许多其他感染的区别在于它们难以用抗生素根除。因此，尽管我们尽了最大的努力，但引起慢性感染的微生物仍会在宿主组织中长期存在。在这些慢性感染的过程中，致病微生物经常发生遗传变化。例如，一种通常感染患有遗传性疾病囊性纤维化（CF）的人的肺部的细菌经历了几种影响这种病原体生长的已知变化。然而，这种和其他慢性感染微生物所经历的变化的原因和临床影响尚不清楚。我们发现，从慢性感染的CF气道分离的细菌中发现的一种常见的早期突变使这些细菌能够更好地在CF肺分泌物中发现的营养物质中生长。有趣的是，这些相同的变化也赋予了对通常用于治疗CF患者的几种抗生素的耐药性。这种突变所赋予的许多特征在慢性感染中发现的其他微生物中也表现出来，这表明这些微生物对宿主组织营养环境的适应可能是慢性感染中抗生素耐药性的常见机制。
Microbes are subjected to selective pressures during chronic infections of host tissues. Pseudomonas aeruginosa isolates with inactivating mutations in the transcriptional regulator LasR are frequently selected within the airways of people with cystic fibrosis (CF), and infection with these isolates has been associated with poorer lung function outcomes. The mechanisms underlying selection for lasR mutation are unknown but have been postulated to involve the abundance of specific nutrients within CF airway secretions. We characterized lasR mutant P. aeruginosa strains and isolates to identify conditions found in CF airways that select for growth of lasR mutants. Relative to wild-type P. aeruginosa, lasR mutants exhibited a dramatic metabolic shift, including decreased oxygen consumption and increased nitrate utilization, that is predicted to confer increased fitness within the nutrient conditions known to occur in CF airways. This metabolic shift exhibited by lasR mutants conferred resistance to two antibiotics used frequently in CF care, tobramycin and ciprofloxacin, even under oxygen-dependent growth conditions, yet selection for these mutants in vitro did not require preceding antibiotic exposure. The selection for loss of LasR function in vivo, and the associated adverse clinical impact, could be due to increased bacterial growth in the oxygen-poor and nitrate-rich CF airway, and from the resulting resistance to therapeutic antibiotics. The metabolic similarities among diverse chronic infection-adapted bacteria suggest a common mode of adaptation and antibiotic resistance during chronic infection that is primarily driven by bacterial metabolic shifts in response to nutrient availability within host tissues. Chronic infections are distinguished from many other infections in that they are difficult to eradicate with antibiotics. Thus, the microbes that cause chronic infections persist within host tissues for long periods despite our best treatment efforts. During the course of these chronic infections, the causative microbes often change genetically. For example, a bacterium that commonly infects the lungs of people with the genetic disease cystic fibrosis (CF) undergoes several known changes that affect the growth of this pathogen. However, the causes and clinical impact of the changes undergone by this and other chronically infecting microbes are unclear. We show that a common, early mutation found in bacteria isolated from chronically infected CF airways renders these bacteria better able to grow in the nutrients found in CF lung secretions. Interestingly, these same changes also confer resistance to several antibiotics used commonly to treat CF patients. Many of the characteristics conferred by this mutation are exhibited by other microbes found in chronic infections, suggesting that adaptation of these microbes to host tissue nutrient environments may be a common mechanism of antibiotic resistance in chronic infections.
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影响因子：
3.2
作者：
Hasset, DJ;Alsabbagh, E;Ochsner, UA
通讯作者：
Ochsner, UA
影响因子：
9.4
作者：
Dénervaud, V;TuQuoc, P;van Delden, C
通讯作者：
van Delden, C
影响因子：
3.8
作者：
Chen, F;Xia, Q;Ju, LK
通讯作者：
Ju, LK
影响因子：
3.2
作者：
Cabrol, SN;Olliver, A;Ruimy, R
通讯作者：
Ruimy, R
DOI：
10.1073/pnas.0800668105
发表时间：
2008-03-18
影响因子：
11.1
作者：
Giannakis, Marios;Chen, Swaine L.;Gordon, Jeffrey I.
通讯作者：
Gordon, Jeffrey I.