Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects.
Alternative Evolutionary Paths to Bacterial Antibiotic Resistance Cause Distinct Collateral Effects.
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DOI：
10.1093/molbev/msx158
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发表时间：
2017-09-01
影响因子：
10.7
通讯作者：
Jansen G
中科院分区：
文献类型：
--
作者：
Barbosa C;Trebosc V;Kemmer C;Rosenstiel P;Beardmore R;Schulenburg H;Jansen G
当细菌进化出对一种特定抗生素的耐药性时，它们可能同时增强对第二种抗生素的敏感性。这种附带敏感性可能被用来开发新的、可持续的抗生素治疗策略，旨在遏制当前急剧蔓延的耐药性。迄今为止，侧枝敏感性的存在和分子基础仅在少数细菌种类中进行了研究，对于铜绿假单胞菌等机会性人类病原体尚不清楚。在本研究中，我们通过实验进化160个独立的铜绿假单胞菌种群对8种常用抗生素的高水平耐药性来评估附带效应的模式。细菌迅速进化出耐药性，并表现出附带敏感性和交叉抗性。这种附带效应的模式与先前报道的其他细菌物种不同，这表明在潜在的进化权衡中存在种间差异。有趣的是，我们还确定了适应同一药物的重复种群中侧枝敏感性和交叉抗性的对比模式。81个独立进化种群的全基因组测序揭示了对选择性药物抗性的不同进化路径，这决定了细菌是否对其他细菌产生交叉耐药或间接敏感。基于基因组和功能遗传学分析，我们证明了侧枝敏感性可能是由调控基因的耐药突变引起的，如nalC或mexZ，它们介导β-内酰胺适应群体对氨基糖苷的敏感性，或双组分调控系统基因pmrB，它增强了庆大霉素耐药群体对青霉素的敏感性。我们的研究结果强调了在重复中进化的附带效应的实质性变化，这反过来决定了它们在抗生素治疗中的潜力。
When bacteria evolve resistance against a particular antibiotic, they may simultaneously gain increased sensitivity against a second one. Such collateral sensitivity may be exploited to develop novel, sustainable antibiotic treatment strategies aimed at containing the current, dramatic spread of drug resistance. To date, the presence and molecular basis of collateral sensitivity has only been studied in few bacterial species and is unknown for opportunistic human pathogens such as Pseudomonas aeruginosa. In the present study, we assessed patterns of collateral effects by experimentally evolving 160 independent populations of P. aeruginosa to high levels of resistance against eight commonly used antibiotics. The bacteria evolved resistance rapidly and expressed both collateral sensitivity and cross-resistance. The pattern of such collateral effects differed to those previously reported for other bacterial species, suggesting interspecific differences in the underlying evolutionary trade-offs. Intriguingly, we also identified contrasting patterns of collateral sensitivity and cross-resistance among the replicate populations adapted to the same drug. Whole-genome sequencing of 81 independently evolved populations revealed distinct evolutionary paths of resistance to the selective drug, which determined whether bacteria became cross-resistant or collaterally sensitive towards others. Based on genomic and functional genetic analysis, we demonstrate that collateral sensitivity can result from resistance mutations in regulatory genes such as nalC or mexZ, which mediate aminoglycoside sensitivity in β-lactam-adapted populations, or the two-component regulatory system gene pmrB, which enhances penicillin sensitivity in gentamicin-resistant populations. Our findings highlight substantial variation in the evolved collateral effects among replicates, which in turn determine their potential in antibiotic therapy.
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影响因子：
14.9
作者：
Balasubramanian D;Schneper L;Kumari H;Mathee K
通讯作者：
Mathee K
DOI：
10.1126/science.aad3292
发表时间：
2016-01-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Baym M;Stone LK;Kishony R
通讯作者：
Kishony R
影响因子：
3.6
作者：
Cao, L;Srikumar, R;Poole, K
通讯作者：
Poole, K
影响因子：
1.2
作者：
Cingolani, Pablo;Platts, Adrian;Ruden, Douglas M.
通讯作者：
Ruden, Douglas M.
影响因子：
10.7
作者：
de Evgrafov, Mari Rodriguez;Gumpert, Heidi;Sommer, Morten O. A.
通讯作者：
Sommer, Morten O. A.