Abstract
Prothionamide (PTH) has been widely used in the treatment of tuberculosis (TB), especially multidrug resistant tuberculosis (MDR-TB), while data regarding prevalence of resistance-causing mutation is limited. In this study, we aimed to investigate the molecular characteristics of PTH-resistant MTB isolates, and also analyzed the risk factors for PTH resistance among Mycobacterium tuberculosis (MTB) isolates in southern China. A total of 282 MTB isolates were enrolled in from Guangzhou Chest Hospital. Among these isolates, 46 (16.3%) were resistant to PTH. Statistical analysis revealed that PTH resistance was more likely to be associated with resistance to levofloxacin (LFX; OR: 2.18, 95% CI: 1.02–4.63; P = 0.04). Of the 46 PTH-resistant MTB isolates, 37 (80.4%) isolates harbored 19 different mutation types, including 10 (21.7%) isolates with double nucleotide substitutions and 27 (58.7%) with single nucleotide substitution. The mutations in ethA (51.4%, 19/37) were most frequently observed among PTH-resistant isolates, followed by 16 (43.2%) in the promoter of inhA and 6 (16.2%) in inhA. In addition, no significant difference was found in the distribution of isolates with different mutation types between Beijing and non-Beijing genotypes (P > 0.05). In conclusion, our data demonstrate that high diversity of genetic mutations conferring PTH resistance is identified among MTB isolates from southern China. Mutations in inhA, ethA, mshA, and ndh genes confer increased resistance of MTB to PTH. Ancient Beijing genotype strains have higher proportion of drug resistance compared with modern Beijing strains. In addition, PTH resistance is more likely to be observed in the LFX-resistant MTB isolates.
Highlights
Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC), continues to be a major cause of morbidity and mortality worldwide, with estimated 9.6 million new cases and 1.5 million deaths reported in 2015 (WHO, 2016)
On the basis of our data, high diversity of genetic mutations conferring PTH resistance is identified among MTB isolates from southern China
The relative long period of KAN implemented for TB treatment may partly explain the current spread of KAN-resistant multidrug resistant tuberculosis (MDR-TB) strains. Another interesting finding of our report was that PTH resistance was more likely to be observed in the LFX-resistant MTB isolates
Summary
Tuberculosis (TB), caused by Mycobacterium tuberculosis complex (MTBC), continues to be a major cause of morbidity and mortality worldwide, with estimated 9.6 million new cases and 1.5 million deaths reported in 2015 (WHO, 2016). Prothionamide (PTH), a member of thioamides, has been widely used for many years in the treatment of MDR-TB, as well as drug susceptible tuberculous meningitis and miliary TB in several settings (Wang et al, 2007; Thee et al, 2016). The genetic mutations in the ethA gene serve as the most important mechanism conferring PTH resistant in MTB. Several novel genes have been identified to be attributed to the decrease in susceptibility to thioamides in MTB, including ethR, mshA, and ndh (DeBarber et al, 2000; Morlock et al, 2003; Vilchèze et al, 2005, 2008; Hazbón et al, 2006)
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