Activities of the semisynthetic glycopeptide LY191145 against vancomycin-resistant enterococci and other gram-positive bacteria

Abstract

LY191145 is the prototype of a series of compounds with activities against vancomycin-resistant enterococci derived by modification of the glycopeptide antibiotic LY264826. LY191145 had MICs for vancomycin-and teicoplanin-resistant enterococci of <4 g/ml for 50% of isolates and <16 g/ml for 90% of isolates. Its MICs for vancomycin-resistant, teicoplanin-susceptible enterococci were 1 to 8 g/ml. LY191145 retains the potent activities of its parent compound against staphylococci and streptococci. In vivo studies in a mouse infection model confirmed these activities. This compound indicates the potential of semisynthetic glycopeptides as agents against antibiotic-resistant gram-positive bacteria.

Intravenous Mouse Infection Model for Studying the Pathology ofEnterococcus faecalisInfections

“…The 50% lethal dose (LD 50 ) of the E. faecalis strains tested in this model was 2.2 ϫ 10 8 to 3.2 ϫ 10 8 CFU/mouse, with the greatest mortality between 24 and 36 h. Intraperitoneal injection of mice with E. faecalis suspended in mucin has been used to induce systemic infection and to evaluate the efficacy of antimicrobial agents. In these experiments, mice were injected intraperitoneally with E. faecalis (5 to 100 LD 50 s, depending on the study) suspended in 5 to 20% hog gastric mucin (6,27,(34)(35)(36)49). These studies used CD1 or ICR mouse strains, and with the exception of one study (Cohen et al [6]) (10 4 to 10 5 CFU/mouse), the number of bacteria injected was not reported.…”

“…Many studies have focused on demonstrating that the presence of specific virulence factors such as aggregation substance, cytolysin, surface protein EspA, and extracellular superoxide production are closely associated with E. faecalis isolates from bacteremic patients (20,21,30,42). Results from these studies suggest that the presence of these virulence factors (or a subset of these factors) may augment the ability of E. faecalis to exist in the bloodstream, since fecal isolates less frequently contain these factors.Animal studies to determine the role of virulence factors in disease (41,45,46) or to study antimicrobial efficacy (5, 6, 34-36) have often relied on intraperitoneal injection of mice with E. faecalis, either alone (23) or in conjunction with a virulence adjuvant such as mucin or sterile rat fecal extracts (5,35,46). Preliminary studies in our laboratory have shown that the use of the intraperitoneal infection model with mucin in BALB/c mice induces a peritoneal inflammatory response that results in adherence of inflammatory cells to the outer surfaces of organs and necrosis.…”

“…Animal studies to determine the role of virulence factors in disease (41,45,46) or to study antimicrobial efficacy (5,6,(34)(35)(36) have often relied on intraperitoneal injection of mice with E. faecalis, either alone (23) or in conjunction with a virulence adjuvant such as mucin or sterile rat fecal extracts (5,35,46). Preliminary studies in our laboratory have shown that the use of the intraperitoneal infection model with mucin in BALB/c mice induces a peritoneal inflammatory response that results in adherence of inflammatory cells to the outer surfaces of organs and necrosis.…”

Telavancin, a Multifunctional Lipoglycopeptide, Disrupts both Cell Wall Synthesis and Cell Membrane Integrity in Methicillin-Resistant Staphylococcus aureus

“…One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).…”

“…Rational approaches toward the design of glycopeptides with improved antimicrobial activities have been described previously (for reviews, see references 35 and 36). One promising approach has been the discovery of lipoglycopeptides, analogs containing hydrophobic groups substituted at the amine position of the disaccharide moiety (20,39,40,45).Telavancin, a semisynthetic derivative of vancomycin possessing a hydrophobic (decylaminoethyl) side chain appended to the vancosamine sugar and a hydrophilic [(phosphonomethyl)aminomethyl] group on the resorcinol-like 4Ј position of amino acid 7 (33), is in late-stage clinical development for the treatment of serious gram-positive infections. Telavancin and other lipoglycopeptides exhibit superior in vitro activity compared to vancomycin (28,30,31,37,39,48), including rapid, concentration-dependent bactericidal activity against glycopeptide-susceptible organisms as well as glycopeptide-intermediate susceptible Staphylococcus aureus and vancomycin-resistant S. aureus (5, 15, 43; K. D. Leuthner, C. M. Cheung, and M. J. Rybak, Abstr.…”