A Bacterial Signaling Network Controls Antibiotic Resistance by Regulating Anaplerosis of 2-oxoglutarate

Hurst, M. N.; Beebout, C. J.; Mersfelder, R.; Hollingsworth, A. N.; Guckes, K. R.; Bermudez, T. A.; Floyd, K. A.; Reasoner, S.; Williams, D. C.; Hadjifrangiskou, M.

doi:10.1101/2020.10.22.351270

bioRxiv · 10.1101/2020.10.22.351270

A Bacterial Signaling Network Controls Antibiotic Resistance by Regulating Anaplerosis of 2-oxoglutarate

Hurst, M. N.·Beebout, C. J.·Mersfelder, R.·Hollingsworth, A. N.·Guckes, K. R.·Bermudez, T. A.·Floyd, K. A.·Reasoner, S.·Williams, D. C.·Hadjifrangiskou, M.

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Abstract

Antibiotic resistance has become a global threat. In addition to acquiring resistance via horizontal gene transfer, bacteria can evade killing by temporarily modifying their cell envelope to prevent antibiotic-bacterial interactions. A critical gap in knowledge is how bacteria balance the metabolic needs of altering the cell envelope with the constant need to generate energy. Cross-regulation between two signaling networks in Escherichia coli increases resistance to positively charged antibiotics. We show that increased resistance is supported by metabolic re-wiring controlled by the QseB transcription factor. QseB controls the increase in 2-oxoglutarate required for lipid A modification, by upregulating three anaplerotic pathways that feed acetyl Co-A, succinate and fumarate into the TCA cycle. Exogenous addition of 2-oxoglutarate restores antibiotic resistance in the qseB deletion mutant. Antibiotic resistant clinical isolates bear mutations within QseB-mediated anaplerotic pathways. These findings are significant, because they uncover a previously unknown mechanism of metabolic control of antibiotic resistance.

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Hurst, M. N., Beebout, C. J., Mersfelder, R., Hollingsworth, A. N., Guckes, K. R., Bermudez, T. A., Floyd, K. A., Reasoner, S., Williams, D. C., Hadjifrangiskou, M.. 2020-10-23. A Bacterial Signaling Network Controls Antibiotic Resistance by Regulating Anaplerosis of 2-oxoglutarate. https://doi.org/10.1101/2020.10.22.351270

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