BVL3572S inhibits HisC and AlaA, exploiting vitamin B6 dependency to kill Mycobacterium tuberculosis
Abstract
Tuberculosis remains the leading cause of death from a single infectious agent, and rising multi-drug resistance in Mycobacterium tuberculosis (Mtb) underscores the urgent need for new antibiotics. Here, we characterize BVL3572S, a hydroxamic acid-containing compound that is bactericidal against Mtb. The primary targets of BVL3572S are the pyridoxal phosphate (PLP; active form of vitamin B6)-dependent aminotransferases HisC (Rv1600) and AlaA (Rv0337c; formerly AspC), simultaneously impacting L-histidine and L-alanine biosynthesis. X-ray crystallography revealed a covalent PLP-BVL3572S adduct within the HisC active site. The formation of the adduct followed by its release suggests a futile cycle that depletes PLP. Consistently, isotopic labeling revealed widespread perturbation of amino acid biosynthesis. CRISPRi and Tn-seq analyses additionally indicated disruptions in central metabolism, cell envelope integrity, and redox balance. BVL3572S displayed strong synergy with the antitubercular drug D-cycloserine. Collectively, our findings establish BVL3572S as a promising lead compound acting through a previously unexploited, multitarget mechanism.
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BibTeX
@article{edoo2026bvl3572s,
title = {{BVL3572S inhibits HisC and AlaA, exploiting vitamin B6 dependency to kill Mycobacterium tuberculosis}},
author = {Zainab Edoo and Astrid Lenne-Delmotte and Camille Grosse and Marie Devaere and Marion Michel and Guillaume Caron and Ernesto Anoz-Carbonell and Kamel Djaout and Rosangela Frita and Cyril Gaudin and Line Hofmann and Sophie Lecher and Véronique Megalizzi and Alessia Michelotti and David Rengel and Pauline Rouan and Stephanie Slupek and Lina Tawk and Rudy Antoine and Hanna Kulyk and Glenn Dale and Christophe Guilhot and Nicolas Willand and Guy Lippens and René Wintjens and Alain Baulard},
journal = {Cell Chemical Biology},
year = {2026},
month = aug,
doi = {10.1016/j.chembiol.2026.07.008},
url = {https://hal.science/hal-05797964v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - BVL3572S inhibits HisC and AlaA, exploiting vitamin B6 dependency to kill Mycobacterium tuberculosis
AU - Zainab Edoo
AU - Astrid Lenne-Delmotte
AU - Camille Grosse
AU - Marie Devaere
AU - Marion Michel
AU - Guillaume Caron
AU - Ernesto Anoz-Carbonell
AU - Kamel Djaout
AU - Rosangela Frita
AU - Cyril Gaudin
AU - Line Hofmann
AU - Sophie Lecher
AU - Véronique Megalizzi
AU - Alessia Michelotti
AU - David Rengel
AU - Pauline Rouan
AU - Stephanie Slupek
AU - Lina Tawk
AU - Rudy Antoine
AU - Hanna Kulyk
AU - Glenn Dale
AU - Christophe Guilhot
AU - Nicolas Willand
AU - Guy Lippens
AU - René Wintjens
AU - Alain Baulard
PY - 2026
DA - 2026/08/11
JO - Cell Chemical Biology
DO - 10.1016/j.chembiol.2026.07.008
UR - https://hal.science/hal-05797964v1
AB - Tuberculosis remains the leading cause of death from a single infectious agent, and rising multi-drug resistance in Mycobacterium tuberculosis (Mtb) underscores the urgent need for new antibiotics. Here, we characterize BVL3572S, a hydroxamic acid-containing compound that is bactericidal against Mtb. The primary targets of BVL3572S are the pyridoxal phosphate (PLP; active form of vitamin B6)-dependent aminotransferases HisC (Rv1600) and AlaA (Rv0337c; formerly AspC), simultaneously impacting L-histidine and L-alanine biosynthesis. X-ray crystallography revealed a covalent PLP-BVL3572S adduct within the HisC active site. The formation of the adduct followed by its release suggests a futile cycle that depletes PLP. Consistently, isotopic labeling revealed widespread perturbation of amino acid biosynthesis. CRISPRi and Tn-seq analyses additionally indicated disruptions in central metabolism, cell envelope integrity, and redox balance. BVL3572S displayed strong synergy with the antitubercular drug D-cycloserine. Collectively, our findings establish BVL3572S as a promising lead compound acting through a previously unexploited, multitarget mechanism.
SN - 2451-9456
SN - 2451-9448
ER -