MDR TB-The Lethal Sound of Silent Mutations

The emergence of the multidrug-resistant tuberculosis (MDR-TB) strains, poses a serious health challenge to developing countries, including Pakistan, which is the 4 th highly vulnerable MDR-TB country in the world.The consistent increase in annual TB rates is due to the emergence of resistance of MDR-TB strains to isoniazid (INH), rifampicin (RIF), streptomycin, pyrazinamide, and ethambutol, the first-line drugs for TB control.In Pakistan, approximately 570,000 TB cases were reported in 2019 with an incidence rate of 263/100,000.It is attributed mostly to a high burden of MDR-TB, RR-TB (rifampicin resistant), as well as isoniazid resistance.Prevalence of pre-XDR-TB (pre-extensive drug resistance) is also reported, including MDR-TB, fluoroquinolone and amikacin, kanamycin, and capreomycin, the second-line injectales.Research around the world has identified that tuberculosis drug resistance is not only caused by inadequate or failed treatment but also due to the molecular basis of drug resistance which includes data on silent mutations concerning first-line TB drugs, leading to transmission of resistant strains.Silent or synonymous mutations, such as those on codon 514 of rpoB, warns the emergence of Mycobacterium tuberculosis rifampin-susceptible strains. 1 Studies from Pakistan have also reported silent mutations at various codons.Sequence analysis of MDR-TB isolates resistant to isoniazid and rifampicin, at codon 528 (CGC to CGT) in the rpoB gene, a silent mutation detected in the RRDR region.2 Another study from Pakistan reported 531 and 513 codon mutations on rpoB gene.A double mutation in the rpoB gene was observed in 12% of the cases.Mutations at codon 315 and 299 of katG gene were observed.The control group had 28.6% MDR positive cases, whereas, the treated group were 100% positive.3 In 2022, the tuberculosis isolated data from Pakistan, from 2003 to 2020 was assessed by using the whole genome sequencing.Microbacterium tuberculosis genetic diversity showed the most significant association with the nusG gene, the potential transmissible phenotype (p = 5.8 × 10 -10) and the cause of circulating drug resistance mutations in Pakistan.