In vitro and in vivo anti-Candida activity and toxicology of LY121019.

Abstract

LY121019 (N-p-octyloxybenzoylechinocandinB nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MICS0 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.25 t g/ml, respectively.Only an 8-fold increase in the MIC against C. albicans occurred during 34-day exposure to subinhibitory concentrations indicating that LY121019 has a low potential for causing resistance development. Scanning electron microscopic studies revealed that LY121019 caused severe damage to the C. albicans cell. The ED50's for LY121019 and amphotericin B administered parenterally to mice were 7.4 and 2.5 mg/kg, respectively. Parenterally administered LY121019 at doses of 6.25 mg/kg significantly reduced the recovery of C. albicans from infected mouse kidneys. Orally administered 50 and 100 mg/kg doses of LY121019 were effective in eliminating C. albicans from the gastrointestinal tract of infected mice. Topical application of 5 % LY12I019 was as effective as 3 % nystatin in the treatment of superficial C. albicans infections. Local administration of LY121019, nystatin, or miconazole was effective against rat vaginal candidiasis. LY121019 was administered intravenously to dogs at doses up to 100 mg/kg/day, 5 days a week for 3 months; all dogs survived. Compound related effects included a histaminelike reaction, increased serum alkaline phosphatase and SGPT, fatty vacuolization of the liver, and some tissue damage at the injection site. The no effect dose in dog was 10 mg/kg. LY121019 had no more than 1/20 the toxicity of amphotericin B in the dog. EchinocandinB and aculeacin are related polypeptide antifungal antibiotics with a narrow spectrum of antifungal activity although highly active against yeasts1.2)• We are reporting on the antiCandida activity and toxicology of LY121019, a novel analog of the polypeptide antifungal antibiotic echinocandin B (Fig. 1). The study involves comparison of the in vitro and in vivo anti-Candida activity and toxicology of LY121019 with these qualities of clinically used parenteral and topical antifungal agents.

Effects of antifungal agents on the function of human neutrophils in vitro

“…In addition, a few other antifungal agents have been developed, some of which may be used in patients who are immunocompromised. These include flucytosine (5-FC); miconazole; and the investigational agents itraconazole (22,27), fluconazole (22,27), cilofungin (LY121019) (14), and Sch-39304 (T. J. Walsh, J. W. Lee, J. Peter, R. Schaufele, M. Rubin, and P. A. Pizzo, Program Abstr. 28th Intersci.…”

Compounds active against cell walls of medically important fungi

“…In particular, the 4-n-octyloxybenzoyl analog cilofungin has generated great interest. In the first reports on this derivative, Gordee et al (94,95) detailed its specific mode of action and determined that the compound had impressive in vitro activity against a variety of Candida spp. and good efficacy in mouse models of systemic and superficial candidiasis.…”

Use of cilofungin as direct fluorescent probe for monitoring antifungal drug-membrane interaction

“…One such target is the plasma membrane-localized (1,3)-3-glucan synthase (GS; EC 2.4.1.34), which catalyzes the biosynthesis of (1,3)-1-glucan, an essential structural polymer of the cell wall (17,36). A number of antifungal drugs have been targeted against GSs from various fungi including the lipopeptide echinocandin-like class of inhibitors (12,30,31,35), aculeacin A (23,24), cilofungin (8,10,11), pneumocandins (12,31), and the papulacandins (2,16,26,37), which are lipid-like saccharides. Each of these compounds contains fatty acid side chains, which have been shown to be essential for the actions of cilofungin (34,38) and papulacandin B (37).…”