Amycolamicin: A Novel Broad-Spectrum Antibiotic Inhibiting Bacterial Topoisomerase

• Published in: Chemistry : a European journal 2012-12, Vol.18 (49), p.15772-15781
• Main Authors: Sawa, Ryuichi, Takahashi, Yoshiaki, Hashizume, Hideki, Sasaki, Kazushige, Ishizaki, Yoshimasa, Umekita, Maya, Hatano, Masaki, Abe, Hikaru, Watanabe, Takumi, Kinoshita, Naoko, Homma, Yoshiko, Hayashi, Chigusa, Inoue, Kunio, Ohba, Syunichi, Masuda, Toru, Arakawa, Masayuki, Kobayashi, Yoshihiko, Hamada, Masa, Igarashi, Masayuki, Adachi, Hayamitsu, Nishimura, Yoshio, Akamatsu, Yuzuru
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Antibiotics; Bacteria; Bacteria - drug effects; Binding; Biophysics; Chemistry; Deoxyribonucleic acid; DNA; DNA replication; DNA Topoisomerase IV - antagonists & inhibitors; DNA Topoisomerase IV - chemistry; Glucosides - chemistry; Glucosides - pharmacology; Inhibitors; Magnetic Resonance Spectroscopy; Methyl alcohol; Microbial Sensitivity Tests; natural products; Pathogens; Pyrroles - chemistry; Pyrroles - pharmacology; Spectrum analysis; Staphylococcus aureus; structure elucidation; Topoisomerase II Inhibitors
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201202645

The abuse of antibacterial drugs imposes a selection pressure on bacteria that has driven the evolution of multidrug resistance in many pathogens. Our efforts to discover novel classes of antibiotics to combat these pathogens resulted in the discovery of amycolamicin (AMM). The absolute structure of AMM was determined by NMR spectroscopy, X‐ray analysis, chemical degradation, and modification of its functional groups. AMM consists of trans‐decalin, tetramic acid, two unusual sugars (amycolose and amykitanose), and dichloropyrrole carboxylic acid. The pyranose ring named as amykitanose undergoes anomerization in methanol. AMM is a potent and broad‐spectrum antibiotic against Gram‐positive pathogenic bacteria by inhibiting DNA gyrase and bacterial topoisomerase IV. The target of AMM has been proved to be the DNA gyrase B subunit and its binding mode to DNA gyrase is different from those of novobiocin and coumermycin, the known DNA gyrase inhibitors. Equilibrium structure: Amycolamicin (AMM) was discovered as a new antibiotic and its absolute structure was determined. The pyranose ring named as amykitanose undergoes anomerization in methanol. AMM is effective against methicillin‐resistant Staphylococcus aureus and its strains, which are resistant to known DNA gyrase inhibitors. AMM is a potent and selective inhibitor of DNA gyrase and it does not inhibit human topoisomerase II (see figure).