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

作者：Tatsuya Kaminishi, Andreas Schedlbauer, Borja Ochoa-Lizarralde, Elisa de Astigarraga, Retina Çapuni, Fred Yang, Vincent Benn, Qingmei Liu, Xiaojuan Tan, Min Zhang, Sean R. Connell, Paola Fucini · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2018 · DOI：10.1101/508218 · 被引用次数：10 · 研究领域：Bacteriophages and microbial interactions、Enzyme Structure and Function、Antibiotic Resistance in Bacteria

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-7072s 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.