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To explore the mechanism of Mycobacterium tuberculosis (Mtb) resistance to fluoroquinolones (FQs) drugs at the genetic level, the whole genome sequencing of fluoroquinolone-resistant Mtb induced in vitro and clinical isolates was conducted.
Mtb standard strain H37Rv was induced into standard levofloxacin (LFX) resistant strain and high-level drug-resistant strain in LJ medium by concentration gradient induction method in vitro. The induced strains and drug-free control strains of each generation were collected and preserved. FQs-resistant strains in clinical isolates were screened, and the sensitivity of the induced strains and clinical isolates to 14 anti-tuberculosis drugs was detected by liquid microplate method, and then the whole genome was sequenced and analyzed.
The analysis of LFX-resistant Mtb model found that the resistance of Mtb to FQs drugs may be related to gene mutations, gyrB (Ala504Thr, Asp461Asn), gyrA (Ala90Val), PE_PGRS31 (Ala395fs), panB (Asp184_Ala187del), aroD (Asp61Asn), devS (Gly348Arg) and rv3446c (Ala178Thr). GWAS analysis of clinical isolates detected 17 new mutation sites that may be related to FQs drug resistance, namely gyrA(p.Glu21Gln, p.Gly668Asp, p.Ser95Thr, p.Glu213Asp, p.His280Arg, p.Ala384Val), gyrB(er132Ala, p.Met291Ile), PE_PGRS31(p.Ser365Phe, p.Pro254Leu, p.Thr252Ile, p.Val352Ile), rv3446c(p.Arg284Pro, p.Leu389Phe, p.Ala164Val) anddevS(p.Val307Ala, p.Ile283Thr).
The LFX-resistant Mtb model constructed in this study provides an ideal biological model for exploring the mechanism of Mtb drug resistance to FQs. Whole genome sequencing has analyzed the mechanism of Mycobacterium tuberculosis resistance to fluoroquinolones from the gene level, and the obtained new mutation sites related to fluoroquinolone resistance still need to be further studied and verified.
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| 科 Family | 属数 Number of genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) | 属 Genus | 种数 Number of species | 占总种数比例 Percentage of total species (%) |
|---|---|---|---|---|---|---|
| 鹅膏菌科Amanitaceae | 2 | 11 | 5.26 | 鹅膏菌属 Amanita | 10 | 4.78 |
| 小菇科 Mycenaceae | 2 | 12 | 5.74 | 丝盖伞属 Inocybe | 5 | 2.39 |
| 多孔菌科 Polyporaceae | 8 | 14 | 6.70 | 蜡蘑属 Laccaria | 5 | 2.39 |
| 红菇科 Russulaceae | 3 | 23 | 11.00 | 小皮伞属 Marasmius | 6 | 2.87 |
| 小菇属 Mycena | 11 | 5.26 | ||||
| 光柄菇属 Pluteus | 5 | 2.39 | ||||
| 红菇属 Russula | 17 | 8.13 | ||||
| 栓菌属 Trametes | 5 | 2.39 |
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