Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.
Systematically Altering Bacterial SOS Activity under Stress Reveals Therapeutic Strategies for Potentiating Antibiotics.
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DOI：
10.1128/msphere.00163-16
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发表时间：
2016-07
期刊：
影响因子：
4.8
通讯作者：
Kohli RM
中科院分区：
文献类型：
--
作者：
Mo CY;Manning SA;Roggiani M;Culyba MJ;Samuels AN;Sniegowski PD;Goulian M;Kohli RM
我们的抗生素库正在逐渐枯竭，部分原因是细菌有能力迅速适应并获得对我们最好的药物的耐药性。SOS通路是细菌中广泛保守的DNA损伤应激反应，被许多抗生素激活，并在促进抗生素应激下的生存和耐药性进化中发挥核心作用。因此，针对SOS反应已被提出作为一种辅助策略，以振兴我们目前的抗生素库。然而，这种方法的最佳分子靶点和合作抗生素仍不清楚。在本研究中，我们针对SOS反应的两个关键调控因子LexA和RecA，首次全面评估了如何靶向SOS反应，以增加抗生素治疗下的细菌敏感性和减少诱变。细菌SOS反应是一个DNA损伤修复网络，在抗菌素应激下与生存和获得性耐药密切相关。因此，两种SOS调节因子，LexA和RecA，已成为旨在对抗耐药性的辅助治疗的潜在靶点，尽管仍存在许多悬而未决的问题。例如，目前尚不清楚SOS过度激活是否是一种可行的治疗方法，或者LexA或RecA是更好的靶点。此外，确定哪些抗菌剂可以作为sos靶向佐剂的最佳治疗伙伴是很重要的。在这里，我们得到了在lexA或recA基因中有突变的大肠杆菌菌株，以覆盖可能的SOS活性水平的全谱。然后，我们通过比较每种药物菌株组合的平均抑制浓度（mic）和诱导突变率，系统地分析了各种抗菌素。我们首先表明，mic的显著变化主要局限于dna损伤抗生素，含有组成性抑制SOS反应的菌株比过度激活的菌株受到更大程度的影响。其次，当SOS活性降低时，抗生素诱导的突变率受到抑制，并且在更广泛的抗生素中观察到这种趋势。最后，干扰LexA或RecA被证明是针对SOS响应的同样可行的策略。我们的工作为多种佐剂策略提供了支持，同时也表明SOS抑制剂与dna损伤抗生素的联合可以提供降低mic和减少获得性耐药的最佳潜力。我们的抗生素库正在逐渐枯竭，部分原因是细菌有能力迅速适应并获得对我们最好的药物的耐药性。SOS通路是细菌中广泛保守的DNA损伤应激反应，被许多抗生素激活，并在促进抗生素应激下的生存和耐药性进化中发挥核心作用。因此，针对SOS反应已被提出作为一种辅助策略，以振兴我们目前的抗生素库。然而，这种方法的最佳分子靶点和合作抗生素仍不清楚。在本研究中，我们针对SOS反应的两个关键调控因子LexA和RecA，首次全面评估了如何靶向SOS反应，以增加抗生素治疗下的细菌敏感性和减少诱变。
Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment. The bacterial SOS response is a DNA damage repair network that is strongly implicated in both survival and acquired drug resistance under antimicrobial stress. The two SOS regulators, LexA and RecA, have therefore emerged as potential targets for adjuvant therapies aimed at combating resistance, although many open questions remain. For example, it is not well understood whether SOS hyperactivation is a viable therapeutic approach or whether LexA or RecA is a better target. Furthermore, it is important to determine which antimicrobials could serve as the best treatment partners with SOS-targeting adjuvants. Here we derived Escherichia coli strains that have mutations in either lexA or recA genes in order to cover the full spectrum of possible SOS activity levels. We then systematically analyzed a wide range of antimicrobials by comparing the mean inhibitory concentrations (MICs) and induced mutation rates for each drug-strain combination. We first show that significant changes in MICs are largely confined to DNA-damaging antibiotics, with strains containing a constitutively repressed SOS response impacted to a greater extent than hyperactivated strains. Second, antibiotic-induced mutation rates were suppressed when SOS activity was reduced, and this trend was observed across a wider spectrum of antibiotics. Finally, perturbing either LexA or RecA proved to be equally viable strategies for targeting the SOS response. Our work provides support for multiple adjuvant strategies, while also suggesting that the combination of an SOS inhibitor with a DNA-damaging antibiotic could offer the best potential for lowering MICs and decreasing acquired drug resistance. IMPORTANCE Our antibiotic arsenal is becoming depleted, in part, because bacteria have the ability to rapidly adapt and acquire resistance to our best agents. The SOS pathway, a widely conserved DNA damage stress response in bacteria, is activated by many antibiotics and has been shown to play central role in promoting survival and the evolution of resistance under antibiotic stress. As a result, targeting the SOS response has been proposed as an adjuvant strategy to revitalize our current antibiotic arsenal. However, the optimal molecular targets and partner antibiotics for such an approach remain unclear. In this study, focusing on the two key regulators of the SOS response, LexA and RecA, we provide the first comprehensive assessment of how to target the SOS response in order to increase bacterial susceptibility and reduce mutagenesis under antibiotic treatment.