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. Ideally, a selectively toxic antifungal agent should be developed that interacts with a fungal target not found in other eukaryotic cells. This strategy involves selective inhibition of the biosynthesis of important structural elements in the fungal cell. The fungal cell wall is such a therapeutic target. In addition, antibiotics have been discovered that inhibit the development of the fungal cell. The major targets are glucan synthesis, inhibited by the echinocandin lipopeptides and the papulacandins; chitin synthesis, inhibited by the polyoxins and nikkomycins; and mannan, to which the pradimicins selectively bind. The extensively studied echinocandin lipopeptides are fungicidal agents with low toxicity, and one member, cilofungin--a semisynthetic analogue of echinocandin B--has been tested in the clinic. Newer echinocandins, such as LY303366 and the pneumocandins, have excellent activity against yeasts and Pneumocystis carinii infections in animals and show promise as potential clinical antifungal candidates. Chitin synthase inhibitors have been studied through chemical modification of the polyoxins and nikkomycins but are limited because of unfavorable pharmacokinetics. The pradimicins show the ability to bind mannan and thus exert an antifungal effect. The mode of action of this class of inhibitors is not fully understood, but their unique action may provide a better understanding of mannan as a target.

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.

A9145is a new adenine-containing antifungal antibiotic. A9145showedweakin vitro activity against Candida albicans in Sabouraud's medium, but was strongly inhibitory in a chemically defined medium. Viability counts of C. albicans following extended exposure to A9145 indicated a fungistatic action. Following a lOOmg/kg dose, a peak of64^g/ml of A9145 activity was detected in mouse blood. Administration of 10 mg/kg for 3 days extended the survival time of mice infected with C. albicans 128 % ; equivalent doses of amphotericin B extended survival time \\2%. A total dose of 31.25mg/kg administered over a 5-day period reduced by 400-fold the number of Candida recovered from kidney homogenates of infected mice. A combination of amphotericin B and A9145 caused a possible synergistic effect against C. albicans in vitro and an additive effect in vivo.

Compound 64716, 1-ethyl-4 (lH)-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. ranged from 2 to 4 and 2 to 8 gg/ml, respectively, and the compound was bactericidal at concentrations close to the minimal inhibitory concentration values. In vivo, doses required for successful therapy of experimental mouse infections were comparable to those for nalidixic acid. After oral administration of 40 mg/kg, peak concentrations of this compound in mouse blood reached 19.2 ,ug/ml. Within 30 min after doses of 20 mg/kg, bacteriologically active drug concentrations of 64716, nalidixic acid, and oxolinic acid in mouse urine were > 1,000, 170, and <1.5 gg/ml, respectively.Resistant bacteria were not selected when bacteria were exposed to 500 ,ug/ml of 64716. Compound 64716 was less bound by human serum proteins than was nalidixic acid. Equivalent antibacterial activity along with superior pharmacological properties of 64716 when compared with nalidixic acid lead to the conclusion that this new compound is a promising antibacterial agent.A series of synthetic organic compounds with cinnoline (1-2-benzodiazine) as the basic ring structure were subjected to bacteriological evaluation. One member of this series, compound 64716, 1-ethyl-4( 1H) -oxo- [1,3]

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