TY - JOUR
T1 - Evybactin is a DNA gyrase inhibitor that selectively kills Mycobacterium tuberculosis
AU - Imai, Yu
AU - Hauk, Glenn
AU - Quigley, Jeffrey
AU - Liang, Libang
AU - Son, Sangkeun
AU - Ghiglieri, Meghan
AU - Gates, Michael F.
AU - Morrissette, Madeleine
AU - Shahsavari, Negar
AU - Niles, Samantha
AU - Baldisseri, Donna
AU - Honrao, Chandrashekhar
AU - Ma, Xiaoyu
AU - Guo, Jason J.
AU - Berger, James M.
AU - Lewis, Kim
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2022/11
Y1 - 2022/11
N2 - The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity. [Figure not available: see fulltext.]
AB - The antimicrobial resistance crisis requires the introduction of novel antibiotics. The use of conventional broad-spectrum compounds selects for resistance in off-target pathogens and harms the microbiome. This is especially true for Mycobacterium tuberculosis, where treatment requires a 6-month course of antibiotics. Here we show that a novel antimicrobial from Photorhabdus noenieputensis, which we named evybactin, is a potent and selective antibiotic acting against M. tuberculosis. Evybactin targets DNA gyrase and binds to a site overlapping with synthetic thiophene poisons. Given the conserved nature of DNA gyrase, the observed selectivity against M. tuberculosis is puzzling. We found that evybactin is smuggled into the cell by a promiscuous transporter of hydrophilic compounds, BacA. Evybactin is the first, but likely not the only, antimicrobial compound found to employ this unusual mechanism of selectivity. [Figure not available: see fulltext.]
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U2 - 10.1038/s41589-022-01102-7
DO - 10.1038/s41589-022-01102-7
M3 - Article
C2 - 35996001
AN - SCOPUS:85137002634
SN - 1552-4450
VL - 18
SP - 1236
EP - 1244
JO - Nature chemical biology
JF - Nature chemical biology
IS - 11
ER -