In Vivo Antibacterial Activity of Vertilmicin,a New Aminoglycoside Antibiotic

Vertilmicin is a novel aminoglycoside antibiotic with potent activity against gram-negative and -positive bacteria in vitro. In this study, we further evaluated the efficacy of vertilmicin in vivo in systemic and local infection animal models. We demonstrated that vertilmicin had relatively high and broad-spectrum activities against mouse systemic infections caused by Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Enterococcus faecalis. The 50% effective doses of subcutaneously administered vertilmicin were 0.63 to 0.82 mg/kg, 0.18 to 0.29 mg/kg, 0.25 to 0.99 mg/kg, and 4.35 to 7.11 mg/kg against E. coli, K. pneumoniae, S. aureus, and E. faecalis infections, respectively. The therapeutic efficacy of vertilmicin was generally similar to that of netimicin, better than that of gentamicin in all the isolates tested, and better than that of verdamicin against E. coli 9612 and E. faecalis HH22 infections. The therapeutic efficacy of vertilmicin was further confirmed in local infection models of rabbit skin burn infection and mouse ascending urinary tract infection.Aminoglycosides are a group of highly potent, broad-spectrum bactericidal antibiotics (8). Their history began with the discovery of streptomycin (12), followed by kanamycin, gentamicin, tobramycin, and a series of semisynthetic aminoglycosides (dibekacin, amikacin, and netilmicin) for the treatment of resistant organisms (8). The mechanisms of aminoglycoside resistance involved (i) modifying enzymes (the most common mechanism), (ii) mutations of the ribosomal binding site (causes resistance to streptomycin), and (iii) reduced drug uptake (mostly seen in Pseudomonas spp.) (2, 13). The semisynthetic aminoglycosides are mainly designed for the treatment of organisms that have developed resistance by producing aminoglycoside-modifying enzymes, i.e., N-acetyltransferase, O-nucleotidyltransferase, and O-phosphotransferases (8).Vertilmicin is a novel semisynthetic aminoglycoside derived from verdamicin. Our earlier study showed that it had broad in vitro antimicrobial activity which is similar to that of netilmicin and has the advantage of lower susceptibility to N-acetyltransferase 6′-Ie modification (5). In this study, we further investigated the in vivo antibacterial activities of this agent in a systemic infection model, as well as local infection models, to fill the gap between in vitro characterization and clinical evaluation. All of our animals studies were approved by the Animal Research Committee of the Institute of Medicinal Biotechnology.