Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.
Ancient and recent differences in the intrinsic susceptibility of Mycobacterium tuberculosis complex to pretomanid.
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DOI：
10.1093/jac/dkac070
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发表时间：
2022-05-29
影响因子：
5.2
通讯作者：
Timm, Juliano
中科院分区：
文献类型：
--
作者：
Bateson, Anna;Canseco, Julio Ortiz;McHugh, Timothy D.;Witney, Adam A.;Feuerriegel, Silke;Merker, Matthias;Kohl, Thomas A.;Utpatel, Christian;Niemann, Stefan;Andres, Sonke;Kranzer, Katharina;Maurer, Florian P.;Ghodousi, Arash;Borroni, Emanuele;Cirillo, Daniela Maria;Wijkander, Maria;Toro, Juan C.;Groenheit, Ramona;Werngren, Jim;Machado, Diana;Viveiros, Miguel;Warren, Robin M.;Sirgel, Frederick;Dippenaar, Anzaan;Koeser, Claudio U.;Sun, Eugene;Timm, Juliano
为最新批准的抗结核药物pretomanid （Pa）开发一种具有正确设置断点的稳健表型抗菌药物敏感性试验（AST）方法。6个实验室使用Becton Dickinson分枝杆菌生长指示管™（MGIT）系统测定356株系统发育多样的结核分枝杆菌复体（MTBC）菌株的mic，以确定pretomanid的流行病学临界值。将MICs与WGS数据进行相关性分析，以研究其易感性差异的遗传基础。我们观察到在MTBC的不同成员之间对pretomanid的易感性存在古代差异。最值得注意的是，估计占全球结核病病例28%的结核分枝杆菌1系比2、3、4和7系更不容易感染，导致1系的第99百分位数为2 mg/L，而其余结核分枝杆菌谱系的第99百分位数为0.5 mg/L。此外，我们观察到较高的mic（≥8mg /L）最近在六种不同的结核分枝杆菌菌株中独立进化，这可能导致耐药性。与上述古代的易感性差异不同，这些最近的差异可能是由已知的pretomanid抗性基因突变引起的。鉴于这些发现，EMA设定的MGIT临时临界浓度为1mg /L必须重新评估。更广泛地说，这些发现强调了在药物临床开发和确定AST断点时考虑MTBC全球多样性的重要性。
To develop a robust phenotypic antimicrobial susceptibility testing (AST) method with a correctly set breakpoint for pretomanid (Pa), the most recently approved anti-tuberculosis drug. The Becton Dickinson Mycobacterial Growth Indicator Tube™ (MGIT) system was used at six laboratories to determine the MICs of a phylogenetically diverse collection of 356 Mycobacterium tuberculosis complex (MTBC) strains to establish the epidemiological cut-off value for pretomanid. MICs were correlated with WGS data to study the genetic basis of differences in the susceptibility to pretomanid. We observed ancient differences in the susceptibility to pretomanid among various members of MTBC. Most notably, lineage 1 of M. tuberculosis, which is estimated to account for 28% of tuberculosis cases globally, was less susceptible than lineages 2, 3, 4 and 7 of M. tuberculosis, resulting in a 99th percentile of 2 mg/L for lineage 1 compared with 0.5 mg/L for the remaining M. tuberculosis lineages. Moreover, we observed that higher MICs (≥8 mg/L), which probably confer resistance, had recently evolved independently in six different M. tuberculosis strains. Unlike the aforementioned ancient differences in susceptibility, these recent differences were likely caused by mutations in the known pretomanid resistance genes. In light of these findings, the provisional critical concentration of 1 mg/L for MGIT set by EMA must be re-evaluated. More broadly, these findings underline the importance of considering the global diversity of MTBC during clinical development of drugs and when defining breakpoints for AST.
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