Amycolamicin

• Project Leader, Hayamitsu Adachi

(Fig.1)

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In the course of our screening program for an agent exhibiting antibacterial activity against MRSA (methicillin-resistant Staphylococcus aureus), VRE (Vancomycin-resistant Enterococci), PRSP (Penicillins-resistant Streptococcus pneumoniae) and BLNAR (β-lactamase-negative ampicillin-resistant Haemophilus influenzae), a novel antibiotic, amycolamicin (AM) was found in a culture broth of a rare actinomycete strain identified as Amycolatopsis sp. MK575-fF5 isolated from soil sample collected in Sendai, Japan. AM has a unique structure which consists of trans-decalin skeleton, tetramic acid, two sugars and pyrrolecarboxylic acid.

AM shows potent and broad antibacterial activity against gram-positive bacteria including MRSA, VRE and PRSP (see table). AM also has the potent antibacterial activity against gram-negative bacteria such as BLNAR.

The toxicological profiles of AM are as follows.

• 1. The lethal dose in mice is more than 250 mg/kg in mice by subcutaneous administration.
• 2. AM induces no genotoxicity for the Ames test.
• 3. AM shows no cytotoxicity at dose of 10 μg/ml for L1210 tumor cell.

AM inhibits bacterial DNA gyrase and topoisomerase IV, but it shows no inhibition against human topoisomerase II. These results and cross resistance experiment suggested that the mode of action of AM is different from that of novobiocin and levofloxacin known as gyrase inhibitor.

AM is a promising lead compound as a novel class of antibiotic. Structure-activity relationship study of AM is now in progress.

Amycolamicin : a novel broad-spectrum antibiotic inhibiting bacterial topoisomerase.
R. Sawa, Y. Takahashi, H. Hashizume,　K. Sasaki,　Y. Ishizaki,　M.Umekita,　M. Hatano,
H. Abe,　T. Watanabe,　N. Kinoshita,　Y. Homma, C. Hayashi,　K. Inoue,　S. Ohba,
T. Masuda,　 M. Arakawa,　Y. Kobayashi,　M. Hamada,　M. Igarashi,　H. Adachi,
Y. Nishimura and Y. Akamatsu.
Chem. Eur. J.  2012, 18, 15772-15781.