The third-generation tetracycline, KBP-7072, exploits and reveals a new potential of the primary tetracycline binding pocket

Kaminishi, T.; Schedlbauer, A.; Ochoa-Lizarralde, B.; de Astigarraga, E.; Capuni, R.; Yang, F.; Benn, V.; Liu, Q.; Tan, X.; Zhang, M.; Connell, S. R.; Fucini, P.

doi:10.1101/508218

bioRxiv · 10.1101/508218

The third-generation tetracycline, KBP-7072, exploits and reveals a new potential of the primary tetracycline binding pocket

Kaminishi, T.·Schedlbauer, A.·Ochoa-Lizarralde, B.·de Astigarraga, E.·Capuni, R.·Yang, F.·Benn, V.·Liu, Q.·Tan, X.·Zhang, M.·Connell, S. R.·Fucini, P.

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Abstract

Antibiotic resistance is a growing threat to human health requiring the discovery or development of new anti-infectives. As such, KBP-7072 is a novel tetracycline derivative that exhibits broad-spectrum activity against Gram-positive and -negative bacterial strains. To determine the mechanism of action of KBP-7072 and understand how its unique C9 extension can be used to combat the growing problem of antibiotic resistance we determined the structure of KBP-7072 bound to the bacterial 30S ribosomal subunit, the inhibitory target of typical tetracyclines. We show that KBP-7072 binds to the primary tetracycline binding site on the 30S ribosomal subunit consistent with it acting as a protein synthesis inhibitor that blocks A-site occupation. Moreover, the unique chemical nature of KBP-7072{acute}s C9 extension leads to a distinctive interaction pattern with the 30S subunit that distinguishes KBP-7072 from the third-generation tetracycline, Tigecycline, and thus expands the interaction potential of the primary tetracycline binding pocket.

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Kaminishi, T., Schedlbauer, A., Ochoa-Lizarralde, B., de Astigarraga, E., Capuni, R., Yang, F., Benn, V., Liu, Q., Tan, X., Zhang, M., Connell, S. R., Fucini, P.. 2018-12-31. The third-generation tetracycline, KBP-7072, exploits and reveals a new potential of the primary tetracycline binding pocket. https://doi.org/10.1101/508218

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