Correlation of gyr Mutations with the Minimum Inhibitory Concentrations of Fluoroquinolones among Multidrug-Resistant Mycobacterium tuberculosis Isolates in Bangladesh

Fluoroquinolone (FQ) compounds-moxifloxacin (MOX), levofloxacin (LEV), and ofloxacin (OFL)-are used to treat multidrug-resistant tuberculosis (MDR-TB) globally. In this study, we investigated the correlation of gyr mutations among Mtb isolates with the MICs of MOX, LEV, and OFL in Bangladesh. A total of 50 MDR-TB isolates with gyr mutations, detected by the GenoType MTBDRsl assay, were subjected to drug susceptibility testing to determine the MICs of the FQs. Spoligotyping was performed to correlate the genetic diversity of the gyr mutant isolates with different MIC distributions. Among the 50 isolates, 44 (88%) had mutations in the gyrA gene, one (2%) had a mutation in the gyrB gene, and five (10%) isolates had unidentified mutations. The substitutions in the gyrA region were at A90V (n = 19, 38%), D94G (n = 16, 32%), D94A (n = 4, 8%), D94N/D94Y (n = 4, 8%), and S91P (n = 1, 2%), compared to the gyrB gene at N538D (n = 1.2%). D94G mutations showed the highest MICs for MOX, LEV, and OFL, ranging between 4.0 and 8.0 mu g/mL, 4.0 and 16.0 mu g/mL, and 16.0 and 32.0 mu g/mL, respectively; while the most common substitution of A90V showed the lowest ranges of MICs (1.0-4.0 mu g/mL, 2.0-8.0 mu g/mL, and 4.0-32.0 mu g/mL, respectively). Spoligotyping lineages demonstrated no significant differences regarding the prevalence of different gyr mutations. In conclusion, the substitutions of codon A90V and D94G in the gyr genes were mostly responsible for the FQs' resistance among Mtb isolates in Bangladesh. Low levels of resistance were associated with the substitutions of A90V, while the D94G substitutions were associated with a high level of resistance to all FQs.

Automated summary

In Bangladeshi Mtb isolates, mutations in the gyr genes at codons A90V and D94G were found to be the main drivers of resistance to fluoroquinolones. A90V mutations were associated with lower levels of resistance, while D94G mutations were associated with high levels of resistance to all fluoroquinolones.