Molecular insights into antibiotic resistance - how a binding protein traps albicidin

Lida Rostock, Ronja Driller, Stefan Grätz, Dennis Kerwat, Leonard Eckardstein, Daniel Petras, Maria Kunert, Claudia Alings, Franz-Josef Schmitt, Thomas Friedrich, Markus C. Wahl, Bernhard Loll, Andi Mainz and Roderich D. Süssmuth ()
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Lida Rostock: Technische Universität Berlin
Ronja Driller: Freie Universität Berlin
Stefan Grätz: Technische Universität Berlin
Dennis Kerwat: Technische Universität Berlin
Leonard Eckardstein: Technische Universität Berlin
Daniel Petras: Technische Universität Berlin
Maria Kunert: Technische Universität Berlin
Claudia Alings: Freie Universität Berlin
Franz-Josef Schmitt: Technische Universität Berlin
Thomas Friedrich: Technische Universität Berlin
Markus C. Wahl: Freie Universität Berlin
Bernhard Loll: Freie Universität Berlin
Andi Mainz: Technische Universität Berlin
Roderich D. Süssmuth: Technische Universität Berlin

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: Abstract The worldwide emergence of antibiotic resistance poses a serious threat to human health. A molecular understanding of resistance strategies employed by bacteria is obligatory to generate less-susceptible antibiotics. Albicidin is a highly potent antibacterial compound synthesized by the plant-pathogenic bacterium Xanthomonas albilineans. The drug-binding protein AlbA confers albicidin resistance to Klebsiella oxytoca. Here we show that AlbA binds albicidin with low nanomolar affinity resulting in full inhibition of its antibacterial activity. We report on the crystal structure of the drug-binding domain of AlbA (AlbAS) in complex with albicidin. Both α-helical repeat domains of AlbAS are required to cooperatively clamp albicidin, which is unusual for drug-binding proteins of the MerR family. Structure-guided NMR binding studies employing synthetic albicidin derivatives give valuable information about ligand promiscuity of AlbAS. Our findings thus expand the general understanding of antibiotic resistance mechanisms and support current drug-design efforts directed at more effective albicidin analogs.

Date: 2018
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DOI: 10.1038/s41467-018-05551-4

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