Mapping the determinants of bedaquiline resistance in Mycobacterium tuberculosis

SUMMARY Bedaquiline (BDQ) is recently developed antibiotic that is used to treat extensively drug-resistant Mycobacterium tuberculosis (Mtb). The vast majority of BDQ resistance mutations are in the non-essential mmpR gene (Rv0678). Resistance to many anti-Mtb drugs can be inferred directly from gene sequences; however, this is not the case for BDQ resistance, largely because there are insufficient data linking specific mmpR mutations with resistance. In this proposal, we will use saturating mutagenesis to create a comprehensive database of mmpR loss-of-function mutations that lead to BDQ resistance. This database can be used together with whole-genome or amplicon sequencing approaches to rapidly diagnose resistance in clinical isolates. In parallel, we will test the ability of this database to predict BDQ resistance in clinical isolates of Mtb. Our long-term goal is to incorporate BDQ resistance profiling into existing genetic analysis pipelines. Project Number: 1R21AI196315-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Joseph Wade | Institution: WADSWORTH CENTER, MENANDS, NY | Award Amount: $403,756 | Activity Code: R21 | Study Section: Anti-Infective Resistance and Targets Study Section [AIRT] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R21AI19631501