Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
Targeting of PBP1 by β-lactams determines recA/SOS response activation in heterogeneous MRSA clinical strains.
复制标题
DOI：
10.1371/journal.pone.0061083
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Rosato AE
中科院分区：
文献类型：
--
作者：
Plata KB;Riosa S;Singh CR;Rosato RR;Rosato AE
SOS反应是细菌中一种保守的调节网络，是对DNA损伤的反应，已被证明与抗生素耐药性的出现有关。以前，我们证明了异质性（HeR）MRSA菌株，当暴露于亚抑制浓度的苯唑西林，能够表达一个同质的高水平的电阻（HoR）。此外，我们发现苯唑西林似乎是β-内酰胺介导的SOS反应的触发因子，通过莱克萨/recA调节剂，负责增加突变率和HoR衍生物的选择。在这项工作中，我们通过选择性地暴露于β-内酰胺和非β-内酰胺细胞壁抑制剂，证明PBP 1在SOS介导的recA激活和HeR-HoR选择中起关键作用。使用可诱导的PBP 1特异性反义构建体对PBP 1进行的功能分析表明，PBP 1消耗消除了β-内酰胺诱导的recA表达/激活，并在HeR/HoR选择期间增加了突变率。此外，基于HeR/HoR选择伴随着PBP 1、PBP 2、PBP 2a和PBP 4表达的补偿性增加的观察结果，我们的研究提供了同时靶向PBP 1和PBP 2或PBP 2a的药剂组合显示出体外和体内功效的证据，从而代表了用于治疗高度耐药HoR-MRSA菌株的治疗选择。从这些研究中收集的信息有助于我们理解β-内酰胺介导的HeR/HoR选择，并提供了新的见解，基于β-内酰胺协同组合，减轻MRSA感染治疗的耐药性。
The SOS response, a conserved regulatory network in bacteria that is induced in response to DNA damage, has been shown to be associated with the emergence of resistance to antibiotics. Previously, we demonstrated that heterogeneous (HeR) MRSA strains, when exposed to sub-inhibitory concentrations of oxacillin, were able to express a homogeneous high level of resistance (HoR). Moreover, we showed that oxacillin appeared to be the triggering factor of a β-lactam-mediated SOS response through lexA/recA regulators, responsible for an increased mutation rate and selection of a HoR derivative. In this work, we demonstrated, by selectively exposing to β-lactam and non-β-lactam cell wall inhibitors, that PBP1 plays a critical role in SOS-mediated recA activation and HeR-HoR selection. Functional analysis of PBP1 using an inducible PBP1-specific antisense construct showed that PBP1 depletion abolished both β-lactam-induced recA expression/activation and increased mutation rates during HeR/HoR selection. Furthermore, based on the observation that HeR/HoR selection is accompanied by compensatory increases in the expression of PBP1,-2, -2a, and -4, our study provides evidence that a combination of agents simultaneously targeting PBP1 and either PBP2 or PBP2a showed both in-vitro and in-vivo efficacy, thereby representing a therapeutic option for the treatment of highly resistant HoR-MRSA strains. The information gathered from these studies contributes to our understanding of β-lactam-mediated HeR/HoR selection and provides new insights, based on β-lactam synergistic combinations, that mitigate drug resistance for the treatment of MRSA infections.
登录
查看更多内容
影响因子：
5.2
作者：
Desbois, Andrew P.;Coote, Peter J.
通讯作者：
Coote, Peter J.
影响因子：
6.7
作者：
Howden BP;McEvoy CR;Allen DL;Chua K;Gao W;Harrison PF;Bell J;Coombs G;Bennett-Wood V;Porter JL;Robins-Browne R;Davies JK;Seemann T;Stinear TP
通讯作者：
Stinear TP
DOI：
10.1016/j.diagmicrobio.2008.04.003
发表时间：
2008-08-01
影响因子：
2.9
作者：
Forbes, Betty A.;Bombicino, Karina;Rosato, Adriana E.
通讯作者：
Rosato, Adriana E.
影响因子：
4.9
作者：
Mehta, Shrenik;Cuirolo, Arabela X.;Rosato, Adriana E.
通讯作者：
Rosato, Adriana E.
影响因子：
3.2
作者：
BOTTA, GA;PARK, JT
通讯作者：
PARK, JT