ArticlePLoS pathogens2020
Predicting nitroimidazole antibiotic resistance mutations in Mycobacterium tuberculosis with protein engineering.
Article in PLoS pathogens, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 81 citations in OpenAlex.
- No phenotypic resistance observed for most group-3 and -4 variants inMicrobiology spectrum · 2026Article
- Rapid detection of treatment-emergent resistance to bedaquiline and pretomanid inMicrobiology spectrum · 2026Article
- Molecular Mechanisms Underlying Antimicrobial Resistance in Mycobacteria.International journal of molecular sciences · 2026Review
- Covalent Inhibitors in Antimicrobial Drug Development-Beyond β-Lactams.Molecules (Basel, Switzerland) · 2026Review
- Whole-Genome Sequencing and Phenotypic Drug Susceptibility Testing of Bedaquilin, Delamanid, Pretomanid, and Linezolid in Drug-ResistantPathogens (Basel, Switzerland) · 2026Article
- Associating Mycobacterium tuberculosis genomic variants with minimum inhibitory concentrations to delamanid and pretomanid.PloS one · 2026Article
- Relapse and Emergent Resistance With Novel Short-Course Regimens for Multidrug-Resistant Tuberculosis, United States, 2022-2024.Open forum infectious diseases · 2026Article
- Key Proteins and Enzymatic Mechanisms Underlying Drug Resistance in Mycobacterium tuberculosis.Advances in experimental medicine and biology · 2026Review
- Article
- Insights into anti-tuberculosis drug design on the scaffold of nitroimidazole derivatives using structure-based computer-aided approaches.RSC advances · 2025Article
- Defining the mechanism of action of the nitrofuranyl piperazine HC2210 against Mycobacterium abscessus.npj antimicrobials and resistance · 2025Article
- Exploring Large Protein Sequence Space through Homology- and Representation-based Hierarchical Clustering.Molecular biology and evolution · 2025Article
- Functions of nitroreductases in mycobacterial physiology and drug susceptibility.Journal of bacteriology · 2025Review
- Structural insights into the enzymatic breakdown of azomycin-derived antibiotics by 2-nitroimdazole hydrolase (NnhA).Communications biology · 2024Article
- Phenotypic-Based Discovery and Exploration of a Resorufin Scaffold with Activity against Mycobacterium tuberculosis.ChemMedChem · 2024Article
- Novel Prodrug Strategies for the Treatment of Tuberculosis.Chemistry, an Asian journal · 2024Review
- Widespread loss-of-function mutations implicating preexisting resistance to new or repurposed anti-tuberculosis drugs.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Article
- Prevalence and genetic basis of Mycobacterium tuberculosis resistance to pretomanid in China.Annals of clinical microbiology and antimicrobials · 2024Article
- Refined understanding of the impact of theMicrobiology spectrum · 2024Article
- Quantitative measurement of antibiotic resistance in Mycobacterium tuberculosis reveals genetic determinants of resistance and susceptibility in a target gene approach.Nature communications · 2024Article
Corrections and comments
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Authors and funding
18 authors at 6 institutions in 4 countries.
Funding
Abstract
Our inability to predict which mutations could result in antibiotic resistance has made it difficult to rapidly identify the emergence of resistance, identify pre-existing resistant populations, and manage our use of antibiotics to effectively treat patients and prevent or slow the spread of resistance. Here we investigated the potential for resistance against the new antitubercular nitroimidazole prodrugs pretomanid and delamanid to emerge in Mycobacterium tuberculosis, the causative agent of tuberculosis (TB). Deazaflavin-dependent nitroreductase (Ddn) is the only identified enzyme within M. tuberculosis that activates these prodrugs, via an F420H2-dependent reaction. We show that the native menaquinone-reductase activity of Ddn is essential for emergence from hypoxia, which suggests that for resistance to spread and pose a threat to human health, the native activity of Ddn must be at least partially retained. We tested 75 unique mutations, including all known sequence polymorphisms identified among ~15,000 sequenced M. tuberculosis genomes. Several mutations abolished pretomanid and delamanid activation in vitro, without causing complete loss of the native activity. We confirmed that a transmissible M. tuberculosis isolate from the hypervirulent Beijing family already possesses one such mutation and is resistant to pretomanid, before being exposed to the drug. Notably, delamanid was still effective against this strain, which is consistent with structural analysis that indicates delamanid and pretomanid bind to Ddn differently. We suggest that the mutations identified in this work be monitored for informed use of delamanid and pretomanid treatment and to slow the emergence of resistance.
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