Rapid evolution of generalized resistance mechanisms can constrain the efficacy of phage-antibiotic treatments.
Rapid evolution of generalized resistance mechanisms can constrain the efficacy of phage-antibiotic treatments.
复制标题
DOI：
10.1111/eva.12653
复制
发表时间：
2018-10
影响因子：
4.1
通讯作者：
Friman VP
中科院分区：
文献类型：
--
作者：
Moulton-Brown CE;Friman VP
据估计，抗生素耐药性每年导致70多万人死亡;因此，迫切需要新的抗菌治疗。提高抗生素效率的一种方法是将它们与细菌特异性寄生病毒（Escherichia coli）结合使用，Escherichia coli已被证明在控制细菌方面发挥累加或协同作用。然而，目前还不清楚这些组合效应在多大程度上受到耐药性快速进化的限制，特别是当病原体在许多持续性和慢性感染的典型表面上作为生物膜生长时。为了研究这一点，我们使用了一个微宇宙系统，其中铜绿假单胞菌PAO 1细菌病原体的遗传等基因群体暴露于噬菌体14/1，庆大霉素或它们两者的组合在空间结构化的环境中。我们发现，即使抗生素和噬菌体抗生素治疗在实验开始时对控制细菌同样有效，但联合治疗在抗生素和生物膜群体中迅速失去其功效。在一种机械的方式，这是由于快速的耐药性演变：虽然抗生素和噬菌体都选择增加自己的阻力，噬菌体选择与抗生素耐药性的增加呈正相关，而生物膜的生长，提供了广义的耐药性机制，是最有利于在组合治疗。只有相对较小的阻力成本和弱证据的共同进化动力学进行了观察。总之，这些结果表明，空间异质性可以促进广义耐药机制的快速进化，而不会相应增加噬菌体感染性，这可能会限制噬菌体抗生素治疗在进化时间尺度上的有效性。
Antimicrobial resistance has been estimated to be responsible for over 700,000 deaths per year; therefore, new antimicrobial therapies are urgently needed. One way to increase the efficiency of antibiotics is to use them in combination with bacteria‐specific parasitic viruses, phages, which have been shown to exert additive or synergistic effects in controlling bacteria. However, it is still unclear to what extent these combinatory effects are limited by rapid evolution of resistance, especially when the pathogen grows as biofilm on surfaces typical for many persistent and chronic infections. To study this, we used a microcosm system, where genetically isogenic populations of Pseudomonas aeruginosa PAO1 bacterial pathogen were exposed to a phage 14/1, gentamycin or a combination of them both in a spatially structured environment. We found that even though antibiotic and phage–antibiotic treatments were equally effective at controlling bacteria in the beginning of the experiment, combination treatment rapidly lost its efficacy in both planktonic and biofilm populations. In a mechanistic manner, this was due to rapid resistance evolution: While both antibiotic and phage selected for increased resistance on their own, phage selection correlated positively with increase in antibiotic resistance, while biofilm growth, which provided generalized resistance mechanism, was favoured most in the combination treatment. Only relatively small cost of resistance and weak evidence for coevolutionary dynamics were observed. Together, these results suggest that spatial heterogeneity can promote rapid evolution of generalized resistance mechanisms without corresponding increase in phage infectivity, which could potentially limit the effectiveness of phage–antibiotic treatments in the evolutionary timescale.
登录
查看更多内容
影响因子：
3.6
作者：
Boles, BR;Thoendel, M;Singh, PK
通讯作者：
Singh, PK
影响因子：
5.8
作者：
Davies, Jane C
通讯作者：
Davies, Jane C
影响因子：
4.8
作者：
Abedon, Stephen T.
通讯作者：
Abedon, Stephen T.
DOI：
10.1098/rspb.2005.3279
发表时间：
2006-01-07
影响因子：
4.7
作者：
Buckling, A;Wei, Y;Hochberg, ME
通讯作者：
Hochberg, ME
噬菌体 - 抗生素协同作用（PAS）：β-内酰胺和喹诺酮抗生素刺激有毒的噬菌体生长。
影响因子：
3.7
作者：
Comeau, Andre M.;Tetart, Francoise;Trojet, Sabrina N.;Prere, Marie-Francoise;Krisch, H. M.
通讯作者：
Krisch, H. M.