Mucoidy, Quorum Sensing, Mismatch Repair and Antibiotic Resistance in Pseudomonas aeruginosa from Cystic Fibrosis Chronic Airways Infections
Mucoidy, Quorum Sensing, Mismatch Repair and Antibiotic Resistance in Pseudomonas aeruginosa from Cystic Fibrosis Chronic Airways Infections
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DOI：
10.1371/journal.pone.0012669
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发表时间：
2010-09-10
期刊：
影响因子：
3.7
通讯作者：
Smania, Andrea M.
中科院分区：
文献类型：
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作者：
Feliziani, Sofia;Lujan, Adela M.;Smania, Andrea M.
铜绿假单胞菌在囊性纤维化(CF)慢性感染中的生存基于特定基因突变的遗传适应过程，这可以产生有利的表型转换，并确保其在肺中持续存在。在这些突变中，最常见的是失活调节因子MUA(藻酸盐生物合成)、LasR(群体感应)和MexZ(多药外排泵Mexxy)的突变，而那些失活DNA错配修复系统(MRS)的突变在铜绿假单胞菌Cf分离株中也非常普遍，导致超突变表型，通过增加突变率来促进这种适应性突变。在这里，我们对从阿根廷患者中分离的铜绿假单胞菌中发现的粘液A、LasR、mexZ和MRS基因的突变进行了特征分析，并分析了粘液A、LasR和mexZ突变与MRS缺乏和抗生素耐药性的潜在关联。因此，从26例慢性感染的CF患者中分离的38株细菌的表型特征、PFGE基因模式、粘蛋白A、LasR、mexZ、MutS和muT L基因编码序列的突变以及抗生素耐药性特征。最常见的突变基因是mexZ(79%)，其次是黏液A(63%)和LasR(39%)，以及由于muL(60%)和MutS(40%)功能丧失突变而观察到的高突变株(42%)。有趣的是，每个基因的突变谱都是特定的，这表明在慢性感染过程中有几种机制导致突变。然而，在粘蛋白A、LasR和mexZ的高突变性和突变之间没有建立联系，这表明MRS缺乏与这些突变的获得无关。最后，尽管先前已证明粘液A、LasR和mexZ的失活会导致对抗生素的耐药性/耐受性，但只有MRS基因的突变可能与抗生素耐药性的增加有关。这些结果有助于揭示导致铜绿假单胞菌适应CF肺的突变动力学。
Survival of Pseudomonas aeruginosa in cystic fibrosis (CF) chronic infections is based on a genetic adaptation process consisting of mutations in specific genes, which can produce advantageous phenotypic switches and ensure its persistence in the lung. Among these, mutations inactivating the regulators MucA (alginate biosynthesis), LasR (quorum sensing) and MexZ (multidrug-efflux pump MexXY) are the most frequently observed, with those inactivating the DNA mismatch repair system (MRS) being also highly prevalent in P. aeruginosa CF isolates, leading to hypermutator phenotypes that could contribute to this adaptive mutagenesis by virtue of an increased mutation rate. Here, we characterized the mutations found in the mucA, lasR, mexZ and MRS genes in P. aeruginosa isolates obtained from Argentinean CF patients, and analyzed the potential association of mucA, lasR and mexZ mutagenesis with MRS-deficiency and antibiotic resistance. Thus, 38 isolates from 26 chronically infected CF patients were characterized for their phenotypic traits, PFGE genotypic patterns, mutations in the mucA, lasR, mexZ, mutS and mutL gene coding sequences and antibiotic resistance profiles. The most frequently mutated gene was mexZ (79%), followed by mucA (63%) and lasR (39%) as well as a high prevalence (42%) of hypermutators being observed due to loss-of-function mutations in mutL (60%) followed by mutS (40%). Interestingly, mutational spectra were particular to each gene, suggesting that several mechanisms are responsible for mutations during chronic infection. However, no link could be established between hypermutability and mutagenesis in mucA, lasR and mexZ, indicating that MRS-deficiency was not involved in the acquisition of these mutations. Finally, although inactivation of mucA, lasR and mexZ has been previously shown to confer resistance/tolerance to antibiotics, only mutations in MRS genes could be related to an antibiotic resistance increase. These results help to unravel the mutational dynamics that lead to the adaptation of P. aeruginosa to the CF lung.