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LY264826 (A82846B) is a naturally-occurring glycopeptide antibiotic, differing from vancomycin in the stereochemistry of the amino-sugar of the disaccharide function, and the presence of a third sugar attached at the benzylic position of amino acid residue 6. Despite these seemingly subtle differences, LY264826 is approximately 10 times more active than vancomycin against the enterococci. In the pursuit of new antibiotics active against multiresistant Gram-positive organisms, an extensive side chain SAR was developed focusing on the reductive alkylation of LY264826 at the amino function of the disaccharide moiety. A new series of derivatives having varying degrees of structural diversity in the side chain (e.g. varying lengths and degrees of rigidity) was found to have potent activity against vancomycin-resistant enterococci (MIC's < 1.0 microgram/ml) as well as activity against staphylococci and streptococci as good or better than vancomycin.

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Reductive alkylation of the A82846 family of glycopeptide antibiotics has the potential of producing seven products. N-Alkylation of the disaccharide amino function can be accomplished selectively, and offers the greatest increase in antibacterial activity. Products resulting from N-alkylation of LY264826 (A82846B) provide the most potent derivatives as compared to other members of this class of antibiotics. Two of these derivatives, LY307599 and LY333328 are approximately 500 times more active than vancomycin against vancomycin-resistant enterococci.

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The antifungal antibiotic, echinocandin B (ECB), was modified by a sequential procedure in which the initial step involved enzymatic removal of the native N-linoleoyl group from the N-terminus using an Actinoplanes utahensis culture. The resulting product, ECB nucleus, was reacylated using active esters or acid halides of various substituted acids to give a series of ECB analogs. These analogs possessed anti-Candida activity both in vitro and in vivo (mice). Other studies have shown that one of these, cilofungin, the 4-n-octyloxybenzoyl-ECB analog (LY121019), has excellent anti-Candida activity, low toxicity and is superior to other available antifungal antibiotics.

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Moxalactam was examined as a substrate for 11 beta-lactamases. Hydrolysis was shown only with the beta-lactamase from Bacillus cereus, a nonpathogenic bacterium. Tobramycin was assayed in tobramycin-moxalactam mixtures by using this beta-lactamase.

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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. albicans. Accumulative doses of 37.5 approximately 600 mg/kg, administered subcutaneously over a 24-hour period, showed significant activity without demonstrating toxicity. A32390A was effective, but not as effective as amphotericin B, in reducing the number of Candida cells isolated from the kidney of infected mice. Urinary excretion of A32390A accounted for only 10% of the administered dose. Improved bioavailability of A32390A was accomplished when the antibiotic was combined with polyvinyl pyrrolidone (PVP) in a solid dispersion. Administration of A32390A as a 10% dispersion in PVP resulted in increased urinary excretion of the drug and reduced the amount of drug required for in vivo activity.

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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. A combination of X irradiation and administration of tobramycin or gentamicin, however, resulted in a stable population of C. albicans in the intestinal tract, with cell counts in the feces remaining constant at a level of about 10(6)/g of feces for a period of 10 to 15 days. The usefulness of this model in assessing the effect of experimental drugs on C. albicans infections of the gut was demonstrated by the fact that treatment with a new antifungal antibiotic (A9145), amphotericin B, 5-fluorocytosine, or nystatin resulted in a reduction in the fecal counts of C. albicans from experimentally infected animals.

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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 0.3 similar to 5.0 mug/ml, Trichophyton mentagrophytes was inhibited at less than 0.0312 mug/ml. Other pathogenic fungi such as Cryptococcus neoformans, Histoplasma capsulatum, Blastomyces dermatitidis, Sporotrichum schenckii, and Microsporium gypseum were very susceptible to A25822B. Only limited antibacterial activity of A25822B was found. Parenteral or oral administration of 50 mg/kg of A25822B significantly extended the average survival time of mice infected with C. albicans. Doses of 20 mg/kg of A25822B caused a greater than ten-fold reduction in the number of Candida cells recovered from kidneys of infected mice. A solution of 0.5% or 0.25% A25822B applied topically was effective against an experimental dermatophyte infection on guinea pigs. A peak blood level of 3 mug/ml was achieved in mice following a 100 mg/kg dose of A25822B. Combination of A25822B with a polyene antibiotic in vitro showed antagonism.

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The dry-heat resistance of Bacillus subtilis var. niger spores located in or on various materials was determined as D and z values in the range of 105 through 160 C. The systems tested included spores located on steel and paper strips, spores located between stainless-steel washers mated together under 150 inch-lb and 12 inch-lb of torque, and spores encapsulated in methylmethacrylate and epoxy plastics. D values for a given temperature varied with the test system. High D values were observed for the systems in which spores were encapsulated or under heavy torque, whereas lower D values were observed for the steel and paper strip systems and the lightly torqued system. Similar z values were obtained for the plastic and steel strip systems (z(D) = 21 C), but an unusually low z for spores on paper (z(D) = 12.9 C) and an unusually high z for spores on steel washers mated at 150 inch-lb of torque (z(D) = 32 C) were observed. The effect of spore moisture content on the D value of spores encapsulated in water-impermeable plastic was determined, and maximal resistance was observed for spores with a water activity (a(w)) of 0.2 to 0.4. Significantly decreased D values were observed for spores with moisture contents below a(w) 0.2 or above a(w) 0.4. The data indicate that the important factors to be considered when measuring the dry heat resistance of spores are (i) the initial moisture content of the spore, (ii) the rate of spore desiccation during heating, (iii) the water retention capacity of the material in or on which spores are located, and (iv) the relative humidity of the system at the test temperature.

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