Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-ß-Lactamase by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting
Trade-Offs Between Antibacterial Resistance and Fitness Cost in the Production of Metallo-ß-Lactamase by Enteric Bacteria Manifest as Sporadic Emergence of Carbapenem Resistance in a Clinical Setting
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肠道细菌生产金属-内酰胺酶的抗菌耐药性和健身成本之间的权衡表现为临床环境中碳青霉烯类耐药性的零星出现
DOI：
10.1101/2020.10.24.353581
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Cheung C
中科院分区：
文献类型：
--
作者：
Cheung C
美罗培南是临床上重要的抗菌药物，用于治疗多重耐药感染。在肠杆菌家族的美罗培南耐药细菌中，尽管两种金属β-内酰胺酶（MBLs）水解美罗培南的动力学几乎相同，但NDM-1比IMP-1更为常见。我们发现blandm -1在野生型肠杆菌中始终赋予美罗培南耐药性，但blaimp -1却没有。原因是blandm -1的表达量较高，因为其启动子较强。然而，美罗培南耐药性的代价是blandm -1阳性肠杆菌的适应度降低。同时，从一个临床病例中，我们发现了多个肠杆菌分离株携带一个编码blandm -1的质粒，该质粒具有一个修饰的启动子区域。这种修饰将MBL产量降低到零适应度成本的水平，但因此，分离株不耐美罗培南。然而，我们从同一临床病例中鉴定出肺炎克雷伯菌分离物携带相同的blandm -1质粒。尽管低水平的NDM-1产生，但由于突变降低了包膜通透性，该分离株对美罗培南具有抗性。因此，总的来说，我们展示了如何解决MBL携带的阻力/适应性权衡。结果是在临床环境中零星出现美罗培南耐药性。
Meropenem is a clinically important antibacterial reserved for treatment of multiresistant infections. In meropenem-resistant bacteria of the familyEnterobacterales, NDM-1 is considerably more common than IMP-1, despite both metallo-β-lactamases (MBLs) hydrolyzing meropenem with almost identical kinetics. We show thatblaNDM-1consistently confers meropenem resistance in wild-typeEnterobacterales, butblaIMP-1does not. The reason is higherblaNDM-1expression because of its stronger promoter. However, the cost of meropenem resistance is reduced fitness ofblaNDM-1-positiveEnterobacterales. In parallel, from a clinical case, we identified multiple Enterobacter spp. isolates carrying a plasmid-encodedblaNDM-1having a modified promoter region. This modification lowered MBL production to a level associated with zero fitness cost, but, consequently, the isolates were not meropenem resistant. However, we identified a Klebsiella pneumoniae isolate from this same clinical case carrying the sameblaNDM-1plasmid. This isolate was meropenem resistant despite low-level NDM-1 production because of aramRmutation reducing envelope permeability. Overall, therefore, we show how the resistance/fitness trade-off for MBL carriage can be resolved. The result is sporadic emergence of meropenem resistance in a clinical setting.