Two Novel katG Mutations Conferring Isoniazid Resistance in Mycobacterium tuberculosis

Abstract

Tuberculosis (TB), an infectious disease caused by Mycobacterium tuberculosis, is among the top 10 leading causes of death worldwide. The treatment course for TB is challenging; it requires antibiotic administration for at least 6 months, and bacterial drug resistance makes treatment even more difficult. Understanding the mechanisms of resistance is important for improving treatment. To investigate new mechanisms of isoniazid (INH) resistance, we obtained three INH-resistant (INH-R) M. tuberculosis clinical isolates collected by the Taiwan Centers for Disease Control (TCDC) and sequenced genes known to harbor INH resistance-conferring mutations. Then, the relationship between the mutations and INH resistance of these three INH-R isolates was investigated. Sequencing of the INH-R isolates identified three novel katG mutations resulting in R146P, W341R, and L398P KatG proteins, respectively. To investigate the correlation between the observed INH-R phenotypes of the clinical isolates and these katG mutations, wild-type katG from H37Rv was expressed on a plasmid (pMN437-katG) in the isolates, and their susceptibilities to INH were determined. The plasmid expressing H37Rv katG restored INH susceptibility in the two INH-R isolates encoding the W341R KatG and L398P KatG proteins. In contrast, no phenotypic change was observed in the KatG R146P isolate harboring pMN437-katG. H37Rv isogenic mutant with W341R KatG or L398P KatG was further generated. Both showed resistant to INH. In conclusion, W341R KatG and L398P KatG conferred resistance to INH in M. tuberculosis, whereas R146P KatG did not affect the INH susceptibility of M. tuberculosis.

Frequency of Mycobacterium tuberculosis in Pneumonia Patients and Prevalence of Virulence Genes

“…The higher number of positive samples are shown by the group of people that suffering from the symptoms for 20 months (6 samples), followed by those who were suffering for 21 months (4 samples), then 19 months (3 samples), then the infection periods 17 and 12 showed 2 samples, and the infection periods 15, 11, and 8 showed only one sample. The results of isolates resistance to Rifampicin and Isoniazid in tabular form (6). The findings revealed that seven percent the positive samples are resistance to Rifampicin and (4%) were sensitive.…”

“…The majority of Mutations in the katG gene, the inhA gene and its promoter, or the oxyR-ahpC region, all of which are involved in cell wall synthesis, confer INH resistance (INH-R) to strains (Hsu et al 2020).…”

Drug-target genes and their spontaneous mutations associated with resistance to first-line, second-line, third-line, novel and repurposed anti-tuberculosis drugs in Mycobacterium tuberculosis resistant strains

“…3,34,37 However, Current research has shown that resistance to isoniazid can also be caused by an upregulation of efflux pumps or isoniazid inactivators. 38,39 Mutations in the katG, inhA and its promoter, and the oxyR-ahpC intergenic region frequently confer resistance to INH. 3,22,29 While mutations in the following genes oxyR, furA, ndh, ahpC, kasA, and fabG1-inhA infrequently confer resistance to INH.…”

New Investigations with Lupane Type A-Ring Azepane Triterpenoids for Antimycobacterial Drug Candidate Design

“…The H37Rv gyrA D94K is a M. tuberculosis strain resistant to moxifloxacin, which contains a mutation of gyrA (D94K) that encodes DNA gyrase subunits and was identified as the most common mechanism to result in fluoroquinolone-resistant tuberculosis [43]. H37Rv katG del is an isoniazid mono-resistant strain containing a catalase-peroxidase (katG) gene mutant associated with cell wall synthesis [44]. The active compounds demonstrated similar activity against the mono-resistant strains (rpoB S450L or gyrA D94K or katG del ).…”