Relationship between structure and biological activity of novel R106 analogs.

The retro-aldol reaction at residue 8 of R106-1 produced a chemical handle, in the form of a sarcosine residue, that was amenable to classical aldol alkylation conditions. In vitro assay of several new hydroxylated analogs have shown that L isomers exhibit more potent antifungal activity than D isomers. However, all analogs exhibited a significant decrease in activity against Cryptococcus neoformans.

Semisynthetic chemical modification of the antifungal lipopeptide echinocandin B (ECB): structure-activity studies of the lipophilic and geometric parameters of polyarylated acyl analogs of ECB.

Echinocandin B (ECB) is a lipopeptide composed of a complex cyclic peptide acylated at the N-terminus by linoleic acid. Enzymatic deacylation of ECB provided the peptide "nucleus" as a biologically inactive substrate from which novel ECB analogs were generated by chemical reacylation at the N-terminus. Varying the acyl group revealed that the structure and physical properties of the side chain, particularly its geometry and lipophilicity, played a pivotal role in determining the antifungal potency properties of the analog.

Antibiotics that inhibit fungal cell wall development.

The discovery of antifungal agents that possess selective toxicity against the eukaryotic fungal cell remains an important scientific challenge. The growing medical need for safe and effective antifungal agents stems from the rapidly increasing population of immunocompromised patients. Although the treatment of fungal infections is progressing steadily, currently available agents act on targets that are also found in mammalian cells.

Antifungal effects of the nonlinear pharmacokinetics of cilofungin, a 1,3-beta-glucan synthetase inhibitor, during continuous and intermittent intravenous infusions in treatment of experimental disseminated candidiasis.

Cilofungin (LY-121019) is a fungicidal cell wall-active 1,3-beta-glucan synthetase inhibitor with a short plasma half-life and saturable nonlinear plasma pharmacokinetics. To optimize the in vivo efficacy of this compound, we studied the effects of its linear and nonlinear pharmacokinetics during continuous versus intermittent intravenous infusion of cilofungin in the treatment of experimental disseminated candidiasis in persistently granulocytopenic rabbits. Six groups of rabbits were studied, untreated controls (n = 32) and five cilofungin dosage regimen groups consisting of the following: 25 mg/kg of body weight intravenously twice daily (VLoINT) (n = 9); 50 mg/kg twice daily (LoINT) (n = 9); 90 mg/kg twice daily (HiINT) (n = 11); 5 mg/kg/h for 18 h/day (LoCI) (n = 7); and 10 mg/kg/h for 18 h/day (HiCI) (n = 7).

Cilofungin (LY121019) shows nonlinear plasma pharmacokinetics and tissue penetration in rabbits.

We studied the plasma pharmacokinetics and tissue penetration of cilofungin (LY121019), a new echinocandin antifungal compound, by intermittent and continuous infusion in rabbits. Following a single intravenous dose of 50 mg/kg of body weight, the maximum concentration in plasma was 297 +/- 39 micrograms/ml, the area under the curve was 30.1 +/- 6.

Fungicidal activity of cilofungin (LY121019) alone and in combination with anticapsin or other antifungal agents.

Cilofungin (LY121019) was shown to have potent fungicidal activity against clinical isolates of Candida albicans and Candida tropicalis but not Candida parapsilosis. Fungicidal activity was evident against both replicating and non-replicating Candida albicans and was progressive over the first 12 h of incubation. The combination of cilofungin (LY121019) with anticapsin but not with amphotericin B, ketoconazole or 5-fluorocytosine resulted in synergistic fungicidal activity.

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

LY121019 (N-p-octyloxybenzoylechinocandin B nucleus) is a semisynthetic antifungal antibiotic that possesses potent anti-Candida activity. The MIC50 and the MIC90 for both LY121019 and amphotericin B were 0.625 and 1.

A32390A, a new biologically active metabolite. III. In vitro and in vivo antifungal activity.

A32390A, an isonitrile-containing derivative of mannitol, represents a new class of antifungal antibiotics. In vitro antifungal activity of A32390A was found against Candida albicans, Cryptococcus neoformans and Histoplasma capsulatum. In vivo antifungal activity of A32390A was demonstrated in mice infected with C.

Colonization of the intestinal tract of conventional mice with Candida albicans and treatment with antifungal agents.

Conventional mice inoculated with Candida albicans per os were unable to maintain this organism in the intestinal tract as judged by decreasing numbers of yeast recoverable from feces. After inoculation with 10(7) cells/mouse, fecal counts ranged from 10(5) cells per g of feces to 5 x 10(3) cells per g of feces during a 12-day experimental period. Addition of various antibiotics to the drinking water did not result in any improvement in maintenance or stability of the gut population.

New azasteroidal antifungal antibiotics from Geotrichum flavo-brunneum. III. Biological activity.

The A25822 antibiotic complex consists of seven biologically active factors. A comparative study of these factors determined that factor B possessed the greatest antifungal activity. The minimal inhibitory concentration of A25822B against isolates of Candida albicans was less than 0.

Cinoxacin: effectiveness against experimental pyelonephritis in rats.

The antimicrobial activity of cinoxacin, 1-ethyl-4(1H)-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid, previously reported as compound 64716, was determined and compared with other antimicrobial agents at a dosage of 12 mg/kg once daily in a descending pyelonephritis rat model with Escherichia coli and Proteus mirabilis as infecting organisms. Cinoxacin was considerably more effective than either nalidixic acid or oxolinic acid when all three were administered orally at 3 mg/kg four times daily. The presence of demonstrable serum activity with a high recovery in urine indicates cinoxacin possesses highly desirable properties of an effective oral chemotherapeutic agent for urinary tract infections.

Compound 64716, a new synthetic antibacterial agent.

Compound 64716, 1-ethyl-4 (1H)-oxo-[1,3]dioxolo[4,5-g]cinnoline-3-carboxylic acid, is a new synthetic antibacterial agent. The antibacterial spectrum of this compound includes gram-negative bacteria that are most frequently isolated from urinary tract infections. Minimal inhibitory concentration values of 64716 for isolates of Escherichia coli and Proteus sp.

New synthetic antibacterial compound, 1-(2-hydroxyethyl)-3-nitro-4-pyrazole carboxamide.

A series of 3-nitropyrazole compounds represent a new class of synthetic antibacterial agents. One member of this series, 1-(2-hydroxyethyl)-3-nitro-4-pyrazolecarboxamide, exhibited an antibacterial spectrum similar to that of nitrofurantoin. The inhibitory concentrations of this nitropyrazole were lower than those required for nitrofurantoin.

Respiratory chain of a pathogenic fungus, Microsporum gypseum: effect of the antifungal agent pyrrolnitrin.

Pyrrolnitrin has been reported to inhibit Bacillus megaterium primarily by forming complexes with phospholipids and to block electron transfer of Saccharomyces cerevisiae between succinate or reduced nicotinamide adenine dinucleotide (NADH) and coenzyme Q. We found that pyrrolnitrin inhibited respiration of conidia of Microsporum gypseum. In mitochondrial preparations, pyrrolnitrin strongly inhibited respiration and the rotenone-sensitive NADH-cytochrome c reductase.

Evaluation of systemic antifungal agents in X-irradiated mice.

The effect of X irradiation on the survival time of animals experimentally infected with pathogenic fungi was studied, and the activity of antifungal agents in pre-irradiated hosts was evaluated. A 24-hr preinfection dose of X irradiation decreased the survival time of mice infected with Cryptococcus neoformans and Histoplasma capsulatum to a greater extent than Candida albicans or Blastomyces dermatitidis infections. Exposure to 400 r caused a significant reduction in the variation (S(2)) survival time of C.

Systemic antifungal activity of pyrrolnitrin.

The antifungal activity of pyrrolnitrin, previously shown to be effective against superficial infections, was evaluated against experimental systemic mycoses. Pyrrolnitrin was inhibitory in vitro at <0.78 to 100 mug/ml to Candida albicans, Cryptococcus neoformans, Blastomyces dermatitidis, Sporotrichum schenckii, and Histoplasma capsulatum.

Relationships of x-irradiation to the enhancement of Candida albicans infections.

Preirradiation significantly reduced the number of Candida albicans cells required for the ld(50) of experimentally infected mice. The start and extent of recovery of total leukocytes of preirradiated infected mice were proportional to the dose of X rays administered. During 10 days postinfection, heterophils of infected mice preirradiated with 400 R recovered to levels above unirradiated, uninfected controls but did not exceed those of unirradiated, infected animals.