Abstract
Mycobacterium tuberculosis resistance to rifampicin is mainly mediated through mutations in the rpoB gene. The effects of rpoB mutations are relieved by secondary mutations in rpoA or rpoC genes. This study aims to identify mutations in rpoB, rpoA, and rpoC genes of Mycobacterium tuberculosis isolates and clarify their contribution to rifampicin resistance. Seventy isolates were identified by acid-fast bacilli smear, Genexpert assay, and growth on Lowenstein Jensen medium. Drug susceptibility, testing was performed by the proportional method. DNA extraction, PCR, and sequencing were accomplished for the entire rpoA, rpoB, and rpoC genes. Twenty-three isolates (32.85%) showed resistance to rifampicin by either proportion method or Genexpert assay. Sequence analysis of the rpoB gene revealed fourteen different mutation patterns. Inside the rifampicin resistance determining region (RRDR), codons: S531L, D516V were highly mutated with frequencies of (21.73%, 17.39%) respectively. Outside the RRDR, there were nine different types of mutations, and M479L was the most prevalent one. Out of 23 RIF resistant isolates, seven isolates (30.43%) carried mutations in the rpoA gene, and twelve isolates (52.17%) harbored a mutation in rpoC. Most of the mutations were identified for the first time in this study. The current study demonstrated that mutations in rpoB, rpoA, and rpoC contributed to RIF resistance in Mycobacterium tuberculosis and this new finding may be relevant to realize how compensatory mutations in the rpoA and rpoC genes restore the fitness cost caused by rifampin resistance-conferring mutations in rpoB.
Highlights
Mycobacterium tuberculosis (M. tuberculosis) causes tuberculosis (TB), which is the leading cause of death by infectious diseases worldwide, with an estimated 10.4 million new TB cases in 2016(1)
To the best of our knowledge, this is the first study in Iraq which deals with rifampicin resistance and its associated genes using sequencing of the entire rpoB, rpoA, and rpoC genes
Five mutation patterns are detected inside the rifampicin resistance determining region (RRDR) of rpoB; the most common is S531L mutation
Summary
Mycobacterium tuberculosis (M. tuberculosis) causes tuberculosis (TB), which is the leading cause of death by infectious diseases worldwide, with an estimated 10.4 million new TB cases in 2016(1). Iraq occupies 108th rank globally and the 7th position among the Eastern Mediterranean Region countries with high TB burden. About 3% of the total cases of TB exist in Iraq. In 2018, WHO estimated that there were 16,000 TB patients in Iraq and deaths due to TB exceeds 4000 annually. The estimated TB incidence rate was 42/100,000. According to the survey of 2014, levels of drug resistance in Iraq was low (1.1%) (WHO). Iraq has a higher incidence rate of TB than all neighboring countries i.e. Syria, Jordan, Iran, Saudi Arabia and Turke [2]
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