Mapping the determinants of bedaquiline resistance in mycobacterium tuberculosis

The National Institute of Allergy and Infectious Diseases awarded Health Research, Inc. (Wadsworth Center Division) $403,756 on April 14, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to map the determinants of bedaquiline resistance in Mycobacterium tuberculosis.

The recipient will use saturating mutagenesis to create a comprehensive database of loss-of-function mutations in the MMPR gene (RV0678) that confer bedaquiline resistance. The database will enable rapid diagnosis of resistance through whole-genome or amplicon sequencing of clinical isolates. In parallel, the recipient will validate the database's predictive accuracy against clinical MTB isolates, with the long-term goal of incorporating bedaquiline resistance profiling into existing genetic analysis pipelines.

Performance occurs at the Wadsworth Center in Albany, New York, with work scheduled through March 31, 2028. The award is a Project Grant, a standard assistance type under the program supporting biomedical research and research training in infectious diseases.

Abstract

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.