Exploiting DprE2 pathway redundancy to enhance potency and overcome resistance to pretomanid in Mycobacterium tuberculosis
Abstract
Tuberculosis (TB), the deadliest infectious disease globally, still poses an enormous public health challenge exacerbated by the rise of multi-drug resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains. The bicyclic nitroimidazoles pretomanid (PTM) and delamanid (DLM) represent the most recent class of anti-tubercular compounds to achieve regulatory approval and clinical implementation in TB chemotherapy regimens. Both are prodrugs whose activity relies on the deazaflavin-dependent nitroreductase Ddn. High-throughput screening on a clinically relevant DdnL49P mutant reveals molecules capable of restoring PTM activity. Optimisation through rational medicinal chemistry leads to highly potent compounds capable of drastically reducing the MIC of PTM while improving its bactericidal activity. Mechanistic studies using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), transposon sequencing and thin-layer chromatography of radiolabeled extracted lipids show that these molecules do not trigger bioactivation pathways, but instead target a compensatory pathway involving Rv2073c, an enzyme that is redundant with DprE2 for bacterial cell wall biosynthesis. The concomitant perturbation of both the DprE2- and Rv2073c-dependent steps by the PTM-NAD adduct and optimised norbornene derivatives leads to a collapse in arabinan synthesis correlating with bacterial death. This study thus highlights Rv2073c as a promising vulnerability that can be exploited to potentiate the efficacy of nitroimidazole anti-tuberculosis drugs
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BibTeX
@article{djaout2026exploiting,
title = {{Exploiting DprE2 pathway redundancy to enhance potency and overcome resistance to pretomanid in Mycobacterium tuberculosis}},
author = {Kamel Djaout and Aurore Dreneau and Léo Faion and Marion Prieri and Maxime Neuville and Alice Boulloy and Alexandre Biela and Rosangela Frita and Marie Devaere and Stephanie Slupek and Rudy Antoine and Ruben C. Hartkoorn and Alexandre Vandeputte and Catherine Piveteau and Florence Leroux and Julie Dumont-Ryckembusch and Adrien Herledan and Adrian Pál and Monika Záhorszká and Katarína Mikušová and Jana Korduláková and Christophe Guilhot and Benoît Déprez and Marion Flipo and Alain Baulard and Nicolas Willand},
journal = {npj Antimicrobials and Resistance},
year = {2026},
month = oct,
doi = {10.1038/s44259-026-00201-y},
url = {https://hal.science/hal-05663291v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Exploiting DprE2 pathway redundancy to enhance potency and overcome resistance to pretomanid in Mycobacterium tuberculosis
AU - Kamel Djaout
AU - Aurore Dreneau
AU - Léo Faion
AU - Marion Prieri
AU - Maxime Neuville
AU - Alice Boulloy
AU - Alexandre Biela
AU - Rosangela Frita
AU - Marie Devaere
AU - Stephanie Slupek
AU - Rudy Antoine
AU - Ruben C. Hartkoorn
AU - Alexandre Vandeputte
AU - Catherine Piveteau
AU - Florence Leroux
AU - Julie Dumont-Ryckembusch
AU - Adrien Herledan
AU - Adrian Pál
AU - Monika Záhorszká
AU - Katarína Mikušová
AU - Jana Korduláková
AU - Christophe Guilhot
AU - Benoît Déprez
AU - Marion Flipo
AU - Alain Baulard
AU - Nicolas Willand
PY - 2026
DA - 2026/10/14
JO - npj Antimicrobials and Resistance
DO - 10.1038/s44259-026-00201-y
UR - https://hal.science/hal-05663291v1
AB - Tuberculosis (TB), the deadliest infectious disease globally, still poses an enormous public health challenge exacerbated by the rise of multi-drug resistant (MDR) and extensively drug-resistant (XDR) M. tuberculosis strains. The bicyclic nitroimidazoles pretomanid (PTM) and delamanid (DLM) represent the most recent class of anti-tubercular compounds to achieve regulatory approval and clinical implementation in TB chemotherapy regimens. Both are prodrugs whose activity relies on the deazaflavin-dependent nitroreductase Ddn. High-throughput screening on a clinically relevant DdnL49P mutant reveals molecules capable of restoring PTM activity. Optimisation through rational medicinal chemistry leads to highly potent compounds capable of drastically reducing the MIC of PTM while improving its bactericidal activity. Mechanistic studies using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), transposon sequencing and thin-layer chromatography of radiolabeled extracted lipids show that these molecules do not trigger bioactivation pathways, but instead target a compensatory pathway involving Rv2073c, an enzyme that is redundant with DprE2 for bacterial cell wall biosynthesis. The concomitant perturbation of both the DprE2- and Rv2073c-dependent steps by the PTM-NAD adduct and optimised norbornene derivatives leads to a collapse in arabinan synthesis correlating with bacterial death. This study thus highlights Rv2073c as a promising vulnerability that can be exploited to potentiate the efficacy of nitroimidazole anti-tuberculosis drugs
SN - 2731-8745
ER -