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rpoB I491F Mutation – Rifampicin Resistance in TB

The rpoB I491F mutation is a genetic change in the rpoB gene of Mycobacterium tuberculosis that can cause rifampicin resistance and is relevant for TB diagnostics.

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Things worth knowing about "rpoB I491F Mutation"

The rpoB I491F mutation is a genetic change in the rpoB gene of Mycobacterium tuberculosis that can cause rifampicin resistance and is relevant for TB diagnostics.

What is the rpoB I491F Mutation?

The rpoB I491F mutation is a specific point mutation in the rpoB gene of Mycobacterium tuberculosis, the bacterium responsible for tuberculosis (TB). In this mutation, the amino acid isoleucine (I) at position 491 of the protein sequence is replaced by phenylalanine (F). The rpoB gene encodes the β-subunit of the bacterial RNA polymerase, which is the primary molecular target of the antibiotic rifampicin.

Relevance to Rifampicin Resistance

Rifampicin is one of the most critical first-line drugs in the treatment of tuberculosis. Mutations in the rpoB gene, including the I491F mutation, can disrupt the binding of rifampicin to the RNA polymerase, thereby conferring rifampicin resistance. Notably, the I491F mutation lies outside the classical Rifampicin Resistance Determining Region (RRDR, codons 507–533), which can make its detection challenging with some standard rapid diagnostic tests.

Clinical Significance

The rpoB I491F mutation is clinically significant as it can be associated with resistance to rifampicin, although in some cases it may present with only low-level or heteroresistant phenotypes. Studies have shown that this mutation is particularly prevalent in certain geographic regions, such as South Africa. Clinical management requires careful phenotypic drug susceptibility testing to accurately determine the sensitivity of the isolated strain to rifampicin and other anti-TB drugs.

Diagnostics

Detection of the rpoB I491F mutation is performed using molecular diagnostic methods, including:

Xpert MTB/RIF Ultra: A widely used rapid nucleic acid amplification test capable of detecting certain rpoB mutations, including I491F.
DNA Sequencing: Enables precise identification of the mutation at the genetic level.
Line Probe Assays (LPA): Molecular strip tests used for mycobacterial resistance determination.

It is important to note that some older or less sensitive rapid tests may not reliably detect the I491F mutation due to its location outside the RRDR. Therefore, extended molecular or phenotypic testing is recommended when rifampicin resistance is suspected.

Treatment Context

When an rpoB I491F mutation is identified, tuberculosis treatment must be individually tailored. Depending on the degree of rifampicin resistance, a switch to second-line therapies used in multidrug-resistant tuberculosis (MDR-TB) may be necessary. Treatment decisions should always be made in consultation with an infectious disease specialist or TB expert, taking into account the results of comprehensive drug susceptibility testing.

References

World Health Organization (WHO): WHO consolidated guidelines on tuberculosis, Module 4: Treatment. Geneva: WHO, 2022.
Meehan CJ et al.: Whole genome sequencing of Mycobacterium tuberculosis: current standards and open issues. Nature Reviews Microbiology, 2019.
Miotto P et al.: A standardised method for interpreting the association between mutations and phenotypic drug resistance in Mycobacterium tuberculosis. European Respiratory Journal, 2017.

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