In vitro activity of tetracycline analogs against multidrug-resistant and extensive drug resistance clinical isolates of Mycobacterium tuberculosis

被引:4
作者
Zhang, Chi [1 ]
Ouyang, Qi [2 ]
Zhou, Xianyuan [1 ]
Huang, Yingfeng [1 ]
Zeng, Yu [1 ]
Deng, Li [1 ]
Lin, Dachuan [2 ]
Zheng, Weidong [1 ]
机构
[1] Shenzhen Univ, Shenzhen Univ Gen Hosp, Dept Lab Med, Shenzhen, Peoples R China
[2] Shenzhen Univ, Sch Med, Dept Pathogen Biol, Guangdong Key Lab Reg Immun & Dis, Shenzhen, Peoples R China
关键词
Tetracycline; Multiple -drug resistance; Doxycycline; Mycobacterium tuberculosis; ANTITUBERCULOSIS DRUGS; ANTIBACTERIAL AGENTS; DOXYCYCLINE; GENES; PHARMACOKINETICS; ANTIBIOTICS; COMBINATION; EXPRESSION; MUTATIONS; PORINS;
D O I
10.1016/j.tube.2023.102336
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Background: Multidrug-resistant tuberculosis (MDR-TB) has become a big threaten to global health. The current strategy for treatment of MDR-TB and extensive drug resistant tuberculosis (XDR-TB) is with low efficacy and high side effect. While new drug is fundamental for cure MDR-TB, repurposing the Food and Drug Administration (FDA)-approved drugs represents an alternative soluation with less cost. Methods: The activity of 8 tetracycline-class antibiotics against mycobacterium tuberculosis (M.tb) were determined by Minimum Inhibitory Concentration (MIC) in vitro. A transposon M.smeg libraries was generated by using the Harm phage and then used to isolate the conditional growth mutants in doxycycline containing plate. Eleven mutants were isolated and genomic DNAs were extracted using the cetyltrimethyl ammonium bromide (CTAB) method and analyzed by whole genome sequencing. Results: We found that three of eight drugs efficiently inhibited mycobacteria growth under the peak plasma concentration in the human body. Further tests showed these three tetracycline analogs (demeclocycline, doxycycline and methacycline) had antimicrobial activity against seven clinical isolates, including MDR and XDR strains. Among them, Doxycycline had the lowest MICs in all mycobacteria strains tested in this study. By using a transposon library, we identify the insertion of transposon in two genes, porin and MshA, associatewith the resistant to doxycycline. Conclusions: Our findings show that tetracycline analogs such as doxycycline, has bactericidal activity against not only drug sensitive M.tb, but also clinical MDR and XDR strains, provided proof of concept to repurpose doxycycline to fight MDR-TB and XDR-TB. Further investigations are warranted to clarify the underlying mechanism and optimize the strategy in combination with other anti-TB drugs.
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