In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates.
In vitro Study of Bedaquiline Resistance in Mycobacterium tuberculosis Multi-Drug Resistant Clinical Isolates.
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DOI：
10.3389/fmicb.2020.559469
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发表时间：
2020
影响因子：
5.2
通讯作者：
Pasca MR
中科院分区：
文献类型：
--
作者：
Degiacomi G;Sammartino JC;Sinigiani V;Marra P;Urbani A;Pasca MR
结核病（TB）是全球与抗菌素耐药性相关的主要死因之一，因为结核分枝杆菌多重和广泛耐药（分别为多重耐药（MDR）和广泛耐药（XDR））临床分离株的传播。为了对抗MDR和XDR结核病，三种新的抗结核病药物贝达喹啉（BDQ）、德拉马尼和pretomanid被批准用于临床。不幸的是，BDQ迅速获得了两种主要的耐药机制，包括编码靶点的atpE基因或编码MmpS 5-MmpL 5外排泵阻遏物的Rv 0678中的突变。为了更好地了解耐多药和广泛耐药结核病中BDQ耐药性的传播，体外研究可能是一个有价值的工具。为此，在这项工作中，在体外产生的M。从作为亲本培养物的两个MDR临床分离株开始进行抗BDQ的结核病突变体的筛选。两个M。结核分枝杆菌MDR临床分离株首次通过全基因组测序进行了表征，找到了导致其MDR表型的主要突变。此外，几个M。结核病BDQ抗性突变体由两种MDR菌株分离，其在atpE和Rv 0678基因中都携带突变。这些BDQ抗性突变体通过研究它们的生长速率进一步表征，所述生长速率可能与它们在临床环境中的传播有关。最后，我们还构建了一个数据表，包括与BDQ耐药相关的突变，这可能有助于MDR/XDR患者中BDQ耐药的早期检测，目的是在临床环境中更好地管理抗生素耐药性。
Tuberculosis (TB) is one of the major causes of death related to antimicrobial resistance worldwide because of the spread of Mycobacterium tuberculosis multi- and extensively drug resistant (multi-drug resistant (MDR) and extensively drug-resistant (XDR), respectively) clinical isolates. To fight MDR and XDR tuberculosis, three new antitubercular drugs, bedaquiline (BDQ), delamanid, and pretomanid were approved for use in clinical setting. Unfortunately, BDQ quickly acquired two main mechanisms of resistance, consisting in mutations in either atpE gene, encoding the target, or in Rv0678, coding for the repressor of the MmpS5-MmpL5 efflux pump. To better understand the spreading of BDQ resistance in MDR- and XDR-TB, in vitro studies could be a valuable tool. To this aim, in this work an in vitro generation of M. tuberculosis mutants resistant to BDQ was performed starting from two MDR clinical isolates as parental cultures. The two M. tuberculosis MDR clinical isolates were firstly characterized by whole genome sequencing, finding the main mutations responsible for their MDR phenotype. Furthermore, several M. tuberculosis BDQ resistant mutants were isolated by both MDR strains, harboring mutations in both atpE and Rv0678 genes. These BDQ resistant mutants were further characterized by studying their growth rate that could be related to their spreading in clinical settings. Finally, we also constructed a data sheet including the mutations associated with BDQ resistance that could be useful for the early detection of BDQ-resistance in MDR/XDR patients with the purpose of a better management of antibiotic resistance in clinical settings.
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影响因子：
158.5
作者：
Conradie, Francesca;Diacon, Andreas H.;Spigelman, Melvin
通讯作者：
Spigelman, Melvin
影响因子：
4.9
作者：
Pang, Yu;Zong, Zhaojing;Huang, Hairong
通讯作者：
Huang, Hairong
影响因子：
3.8
作者：
Li, Yang;Sun, Feng;Zhang, Wenhong
通讯作者：
Zhang, Wenhong
影响因子：
3.2
作者：
Martinez, Elena;Hennessy, Daneeta;Sintchenko, Vitali
通讯作者：
Sintchenko, Vitali
影响因子：
7.5
作者：
Pontali, Emanuele;Raviglione, Mario C.;Migliori, Giovanni Battista;Akkerman, Onno W.;Alffenaar, Jan-Willem;Blanc, Francois Xavier;Borisov, Sergey;Cirillo, Daniela Maria;Dalcolmo, Margareth;Dheda, Keertan;Kritski, Afranio L.;Lienhardt, Christian;Olliaro, Piero;Tadolini, Marina;Tiberi, Simon;Udwadia, Zarir
通讯作者：
Udwadia, Zarir