Svanberg Frisinger Frida, Pirolo Mattia, Ng Duncan Y K, Mao Xiaotian, Nielsen Dennis Sandris, Guardabassi Luca
Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, 1870 Frederiksberg, Denmark.
Department of Bacteria, Parasites and Fungi, Statens Serum Institut, 2300 Copenhagen, Denmark.
Pharmaceuticals (Basel). 2022 Jun 9;15(6):731. doi: 10.3390/ph15060731.
New Gram-negative-selective antimicrobials are desirable to avoid perturbations in the gut microbiota leading to antibiotic-induced dysbiosis. We investigated the impact of a prototype drug (MAC13243) interfering with the Gram-negative outer membrane protein LolA on the faecal microbiota. Faecal suspensions from two healthy human donors were exposed to MAC13243 (16, 32, or 64 mg/L) using an in vitro gut model (CoMiniGut). Samples collected 0, 4, and 8 h after exposure were subjected to viable cell counts, 16S rRNA gene quantification and V3-V4 sequencing using the Illumina MiSeq platform. MAC13243 exhibited concentration-dependent killing of coliforms in both donors after 8 h. Concentrations of ≤32 mg/L reduced the growth of aerobic bacteria without influencing the microbiota composition and diversity. An expansion of Firmicutes at the expense of Bacteroidetes and Actinobacteria was observed in the faecal microbiota from one donor following exposure to 64 mg/L of MAC13242. At all concentrations tested, MAC13243 did not lead to the proliferation of nor a reduced abundance of beneficial bacteria, which are typical changes observed in antibiotic-induced dysbiosis. These results support our hypothesis that a drug interfering with a specific target in Gram-negative bacteria has a low impact on the commensal gut microbiota and, therefore, a low risk of inducing dysbiosis.
新型革兰氏阴性菌选择性抗菌药物有助于避免肠道微生物群紊乱，从而避免抗生素引起的生态失调。我们研究了一种原型药物（MAC13243）干扰革兰氏阴性菌外膜蛋白LolA对粪便微生物群的影响。使用体外肠道模型（CoMiniGut）将两名健康人类供体的粪便悬液暴露于MAC13243（16、32或64 mg/L）。暴露后0、4和8小时收集的样本进行活菌计数、16S rRNA基因定量，并使用Illumina MiSeq平台进行V3-V4测序。8小时后，MAC13243在两名供体中均表现出对大肠菌群的浓度依赖性杀灭作用。≤32 mg/L的浓度可降低需氧菌的生长，而不影响微生物群的组成和多样性。在一名供体的粪便微生物群中，暴露于64 mg/L的MAC13242后，观察到厚壁菌门以拟杆菌门和放线菌门为代价的扩张。在所有测试浓度下，MAC13243均未导致有益细菌的增殖或丰度降低，而这些是抗生素引起的生态失调中常见的变化。这些结果支持了我们的假设，即一种干扰革兰氏阴性菌特定靶点的药物对共生肠道微生物群的影响较小，因此诱导生态失调的风险较低。
