In vitro antifungal activities and in vivo efficacies of 1,3-beta-D-glucan synthesis inhibitors L-671,329, L-646,991, tetrahydroechinocandin B, and L-687,781, a papulacandin

Abstract

The in vivo anti-Candida activities of 1,3-13-D-glucan synthesis inhibitors L-671,329, L-646,991 (cilofungin), L-687,901 (tetrahydroechinocandin B), and L-687,781 (a papulacandin analog) were evaluated by utilizing a murine model of disseminated candidiasis that has enhanced susceptibility to Candida albicans but increased sensitivity for discriminating antifungal efficacy. DBA/2 mice were challenged intravenously with 1 x 104 to 5 x 104 CFU of C. albicans MY1055 per mouse. Compounds were administered intraperitoneally at concentrations ranging from 1.25 to 10 mg/kg of body weight twice daily for 4 days. At 6 h and 1, 2, 3, 4, 7, and 9 days after challenge, five mice per group were sacrificed and their kidneys were homogenized and plated for enumeration of Candida organisms (CFU per gram). Progressiveness of response trends and no-statisticalsignificance-of-trend doses were derived to rank compound efficacy. 1,3-13-D-Glucan synthesis 50% inhibitory concentrations were determined by using a C. albicans (MY1208) In the last decade, the incidence of serious fungal infections has reached record levels. This increase is due primarily to the AIDS epidemic, an expanding number of immune deficiency syndromes, and modern medical techniques that predispose a much larger population to opportunistic fungal infections. The number of current therapies available to counter the mycoses has been developed at approximately the same rate since the inception of antifungal drug therapy. Amphotericin B (AMB), developed in the 1950s, still remains the drug of choice for most fungal diseases mainly because it is broad spectrum and fungicidal, but it is considered to be relatively toxic (36, 37). The broad-spectrum azole antifungal agents developed more recently, although considered to be safer and less toxic than AMB, are fungistatic, which has limited their utility in many clinical settings (28,36). Many of these new antifungal agents are ineffective against deep-seated, life-threatening mycoses. Therefore, the critical need for new fungicidal agents which are safe and effective is evident.Our efforts toward identification of a promising antifungal agent have focused on 1,3-p-D-glucan synthesis inhibitors.

Differential Activities of Three Families of Specific β(1,3)Glucan Synthase Inhibitors in Wild-type and Resistant Strains of Fission Yeast

“…The MIC values of papulacandin and aculeacin described for S. cerevisiae and Candida are similar to the values for S. pombe (11,25,47,48). In other cases, the MIC value of a specific inhibitor fluctuate, depending on the method of analysis, the strain, or the organism.…”

Increased antifungal activity of L-733,560, a water-soluble, semisynthetic pneumocandin, is due to enhanced inhibition of cell wall synthesis

“…The in vitro antifungal susceptibilities of Candida albicans, S. cerevisiae, and Aspergillus fumigatus to the pneumocandins were determined (see Table 1). Yeast Nitrogen Base (Difco) with 2% glucose was used for MIC and minimum fungicidal concentration (MFC) determinations by a previously described broth microdilution assay (5). Briefly, 104 yeast or conidia were inoculated into 0.15 ml of medium containing twofold serial dilutions of test compound.…”

Structural and Biological Characterization of Chromofungin, the Antifungal Chromogranin A-(47–66)-derived Peptide

“…Antimicrobial agents are classified as inhibitors for microbial cell metabolism (9), lytic peptides that disrupt the membrane structure (10), inhibitors for protein biosynthesis, and inhibitors for DNA and RNA synthesis (11). The present work was carried out to understand the molecular mechanisms involved in the antifungal activity of the C-terminal region of vasostatin-I; we sought the most active fragment and found the CGA-(47-66) peptide to be the shortest potent one.…”