Alternative selection factors for bedaquiline resistance
Multidrug resistant tuberculosis (MDR-TB) is an issue of increasing urgency. Many of the antibiotics used to treat Mycobacterium tuberculosis (TB) are decreasing in their efficacy. Bedaquiline (BDQ) is an antibiotic used to treat many strains of MDR- TB and is used as a last-line-of-defense antibiotic. However, since its approval in 2012, there have been an increasing number of TB strains discovered to possess mutations in the rv0678 gene causing BDQ resistance. It is important to note that some rv0678 mutations are arising in strains of TB that have not been exposed to BDQ, and if these rv0678 mutations are already present prior to exposure to BDQ, then the efficacy of BDQ treatment is decreased. Rifampin (RIF) is a first-line antibiotic that is commonly used to treat TB. In a prior study conducted at TGen North, a mixture of wild type TB and rv0678 mutant was incubated with RIF for 30 days. After 30 days, the culture showed positive selection for the rv0678 mutation. Most strains of MDR-TB have been exposed to RIF. Thus, if RIF can select for rv0678 mutations, then the use of RIF could hinder the action of BDQ. Currently, experimentation is underway to determine if RIF can select for rv0678 mutations that arise de novo. A wild-type, attenuated TB culture was treated with varying concentrations of RIF (inhibitory and sub-inhibitory). Over the course of one month, weekly DNA extractions and amplicon sequencing were used to screen for mutations. Low levels of a rv0678 mutation in a culture treated with a sub-inhibitory concentration of RIF were found. Selection for this mutation at low concentrations of RIF could indicate that treatment noncompliance with RIF is a risk factor for BDQ resistance.
