Elucidating the molecular mechanisms underlying mutations in Mycobacterium tuberculosis RNA polymerase that confer resistance to rifampicin and its structural analogues

Tuberculosis (TB) is a major global health problem caused by Mycobacterium tuberculosis (Mtb), and is responsible for significant morbidity and mortality worldwide. Rifampicin and its structural analogues are essential first-line anti-TB drugs that inhibit RNA synthesis by binding to the beta-subunit of Mtb RNA polymerase (RNAP). However, the emergence of rifampicin resistant Mtb strains poses a major challenge for TB control efforts. Mutations in the rpoB gene encoding the beta-subunit of RNAP are the most common cause of rifampicin resistance in Mtb. Understanding the molecular mechanisms underlying these mutations and their effects on RNAP function is crucial for developing new drugs and combination therapies to overcome rifampicin resistance in Mtb. This review discusses the molecular mechanisms underlying rifampicin resistance in Mtb RNAP, including the genetic basis and identification of mutations. It can be hypothesized that rifampicin resistance in Mtb RNAP is a multifactorial phenomenon involving structural, biochemical, and genetic factors. The review highlights strategies for developing new drugs and combination therapies to overcome rifampicin resistance in Mtb and future directions for research on the molecular mechanisms underlying rifampicin resistance in Mtb RNAP.