Synthesis and preliminary biological characterization of new semisynthetic derivatives of ramoplanin.
Ramoplanin is a glycolipodepsipeptide antibiotic active against Gram-positive bacteria including vancomycin-resistant enterococci. Ramoplanin inhibits bacterial cell wall biosynthesis by a mechanism different from that of glycopeptides and hence does not show cross-resistance with these antibiotics. The systemic use of ramoplanin has been so far prevented because of its low local tolerability when injected intravenously. To overcome this problem, the fatty acid side chain of ramoplanin was selectively removed and replaced with a variety of different carboxylic acids. Many of the new ramoplanin derivatives showed antimicrobial activity similar to that of the natural precursor coupled with a significantly improved local tolerability. Among them the derivative in which the 2-methylphenylacetic acid has replaced the di-unsaturated fatty acid side chain (48) was selected as the most interesting compound and submitted to further in vitro and in vivo characterization studies.
Ciabatti
Romeo
R
Vicuron Pharmaceuticals, Gerenzano, Varese, Italy. Romeo.Ciabatti@hotmail.it
Maffioli
Sonia I
SI
Panzone
Gianbattista
G
Canavesi
Augusto
A
Michelucci
Elena
E
Tiseni
Paolo S
PS
Marzorati
Ettore
E
Checchia
Anna
A
Giannone
Matteo
M
Jabes
Daniela
D
Romano
Gabriella
G
Brunati
Cristina
C
Candiani
Gianpaolo
G
Castiglione
Franca
F
D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002176:Candida albicans / Q000187:drug effects; D047630:Depsipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013293:Enterococcus faecalis / Q000187:drug effects; D006461:Hemolysis; D008826:Microbial Sensitivity Tests; D051381:Rats; D013211:Staphylococcus aureus / Q000187:drug effects; D013237:Stereoisomerism; D013297:Streptococcus pyogenes / Q000187:drug effects; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D047630:Depsipeptides; C041438:ramoplanin