Fluoroquinolone resistance and mutational profile of gyrA in pulmonary MDR tuberculosis patients

Abstract

Background Fluoroquinolones (FQs) are potential drugs that inhibit DNA synthesis and are used in the treatment of multidrug-resistant tuberculosis (TB) and short-term anti-TB regimens. In recent years, a high proportion of FQ resistance has been observed in Mycobacterium tuberculosis isolates. The development of FQ resistance in multidrug-resistant TB negatively impacts patient treatment outcome and is a serious threat to control of TB. Methods The study included a total of 562 samples from patients with pulmonary TB that had been on anti-tuberculosis therapy. MTBDRsl assays were performed for the molecular detection of mutations. Sequence analysis was performed for the characterization and mutational profiling of FQ-resistant isolates. Results FQ resistance was observed in 104 samples (18.5%), most of which were previously treated and treatment failure cases. A total of 102 isolates had mutations in DNA gyrase subunit A (gyrA), while mutations in gyrB were observed in only two isolates. Mutational analysis revealed that the mutations mostly alter codons 94 (replacing aspartic acid with glycine, D94G) and 90 (replacing alanine with valine, A90V). In MDR and treatment failure cases, resistance to FQs was most commonly associated with the D94G mutation. In contract, a high proportion of A90V mutations were observed in isolates that were newly diagnosed. Conclusion The findings suggest that genotypic assays for FQ resistance should be carried out at the time of initial diagnosis, before starting treatment, in order to rule out mutations that impact the potential use of FQs in treatment and to control drug resistance.

A precision overview of genomic resistance screening in isolates ofMycobacterium tuberculosisusing web-based bioinformatics tools

“…Our results when applying WGS show that 92.3% of mutations were presented in the gyrA gene, especially in the quinolone resistance-determining region (QRDR) D89G, A90V and D94N codons and one isolate presented combined mutations D94A into gyrA gene plus N499D in gyrB. This is in concordance with various studies that reported mutations in the conserved QRDR region of gyrase genes (gyrA and gyrB) which changes the structure of the drug binding pocket (QBP) and results in cross-resistance to all FQs (64,(77)(78)(79). One resistant isolate did not have gyrA or gyrB mutations.…”

Comparative genomics of drug-resistant strains of Mycobacterium tuberculosis in Ecuador

“…Finally, in ethambutol, most resistance-related genes are located on the embB, embC, and upstream of the embA [74,75]. Meanwhile, previous studies have agreed that the genes rrs, rpsL, and gid are related to different levels of streptomycin resistance [76,77], and the chromosomal mutations in the quinolone resistance determining region of gyrA or gyrB are the main mechanism of resistance to fluoroquinolones in M. tuberculosis [78,79]. In our study, we found 57.1%, 70.0%, 47.6%, and 28.6% and 28.45% of mutations S450L (rpoB), S315T/G (katG), M306V/I (embB), K43R (rpsL) and c492t, a514c (rrs locus) related to rifampicin, isoniazid, ethambutol, streptomycin and fluoroquinolones resistance respectively.…”