PanB over-representation as part of pyrazinamide action: a proteomic insight

Background: Pyrazinamide (PZA) represents a milestone as a first-line antituberculosis drug due to its sterilizing activity against Mycobacterium tuberculosis. Materials & Methods: The protein changes induced by subinhibitory PZA exposure of M. tuberculosis in acidic pH were evaluated by a proteomic approach. Results: Among the 1059 M. tuberculosis proteins identified, the specific acidification in the culture medium induced the over-representation of MurF (Rv2157c), and its underrepresentation was induced by 12 h of PZA exposure. PanB (Rv2225) was over-represented at 24 h of PZA exposure. Conclusion: The authors highlight the over-representation of PanB in M. tuberculosis correlates of PZA action in acidic pH, reinforcing the role of the pantothenate pathway as a bacillus drug target to be explored.

Comprehensive Assessment of the Safety of a New Antituberculosis Drug from the Diarylquinolines Group

The safety of the new anti-tuberculosis drug Tiozonide was studied by bioinformatics and preclinical methods using laboratory animals and with the participation of healthy volunteers. The absence of toxic effects on the main life support systems of mammals predicted by QSAR models was confi rmed by the results of acute, subchronic and chronic toxicity tests in various laboratory animals. Monitoring of the vital indicators of volunteers and a comparative analysis of the generalized results of these indicators before (screening), during and after the study showed the absence of reliable and clinically signifi cant changes that threaten the life and health of people.

ANTITUBERCULOSIS DRUG ALLERGY IN PATIENTS WITH MULTIDRUG-RESISTANT TUBERCULOSIS

To identify allergic reactions (AR) to anti-tuberculosis drugs (ATD) in patients with multidrug-resistant tuberculosis (MDR-TB).

Correction: Predicting Antituberculosis Drug–Induced Liver Injury Using an Interpretable Machine Learning Method: Model Development and Validation Study (Preprint)

UNSTRUCTURED Description: The corresponding author should be Shenyuan Liu. The 2 and 7 authors’ affiliation missing China. The 3-5 authors’ affiliation should be Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, China.

Genetic and Functional Evaluation of the Role of FOXO1 in Antituberculosis Drug-Induced Hepatotoxicity

Background. The accumulation of the hepatotoxic substance protoporphyrin IX (PPIX) induced by aminolevulinate synthase 1 (ALAS1) activation is one of the important mechanisms of antituberculosis drug-induced hepatotoxicity (ATDH). Forkhead box protein O1 (FOXO1) may activate ALAS1 transcription. However, little is known about their roles in ATDH; we performed a study to determine the association between polymorphisms in the two genes and ATDH susceptibility. Then, we verified this possible association by cellular functional experiments. Materials and Methods. Tag single-nucleotide polymorphisms (TagSNPs) in the two genes were genotyped in 746 tuberculosis patients. The frequencies of the alleles, genotypes, genetic models, and haplotype distribution of the variants were compared between the case and control groups. L-02 cells and HepG2 cells were incubated with the indicated concentration of isoniazid (INH) and rifampicin (RIF) for the desired times, and then the expression levels of ALAS1 and FOXO1 mRNAs and proteins were detected. HepG2 cells were transiently transfected with FOXO1 siRNA to observe the effect of changes in the FOXO1 expression on the cell survival rate and ALAS1 expression. Results. The C allele at rs2755237 and the T allele at rs4435111 in the FOXO1 gene were associated with a decreased risk of ATDH. The expression of ALAS1 in both L-02 cells and HepG2 cells was increased by the coadministration of INH/RIF (600/200 μM) for 24 h. Although FOXO1 expression was reduced slightly by the same treatment, its content in the nucleus was significantly increased. However, the cell survival rate and ALAS1 expression level were not significantly altered by the downregulation of FOXO1 in HepG2 cells. Conclusions. Variants of the rs4435111 and rs2755237 loci in the FOXO1 gene were associated with susceptibility to ATDH. Coadministration of INH/RIF promoted the transfer of FOXO1 from the cytoplasm to the nucleus, but the functional significance of its nuclear translocation requires further verification.