Disease relevance of AIDS008670

• A pathway-specific transcriptional regulatory gene for nikkomycin biosynthesis in Streptomyces ansochromogenes that also influences colony development [1].
• Use of the chitin-synthesis inhibitor nikkomycin to treat disseminated candidiasis in mice [2].
• Efficacy of nikkomycin Z against experimental pulmonary blastomycosis [3].
• Efficacy of nikkomycin Z in the treatment of murine histoplasmosis [4].
• In vivo, nikkomycin Z was more effective than nikkomycin X, was also found to be superior on a milligram per milligram basis to the majority of azoles tested in the models of coccidioidomycosis and blastomycosis, and was moderately effective in histoplasmosis [5].

High impact information on AIDS008670

• Calcofluor staining of the chs-1RIP strain cross-walls, residual chitin synthase activity, and the increased sensitivity of the chs-1RIP strain to Nikkomycin Z suggest that N. crassa produces additional chitin synthase that can participate in cell wall formation [6].
• In cultures started with unbudded cells, an inhibitor of Chs3p activity, nikkomycin Z, aggravated the abnormalities of cla4 and cdc11 mutants and gave rise to enlarged necks at the mother-bud junction, leading to cell death [7].
• DNA sequence analysis of a 7.5 kb XhoI DNA fragment from the region flanking the nikkomycin biosynthesis gene cluster in Streptomyces ansochromogenes revealed one 3.3 kb open reading frame (ORF), designated sanG [1].
• Phosphorylation of Mpk1 is induced in response to perturbations of cell wall biosynthesis by the antifungal drugs nikkomycin Z (a chitin synthase inhibitor), caspofungin (a beta-1,3-glucan synthase inhibitor), or FK506 (a calcineurin inhibitor), and mutants lacking Mpk1 display enhanced sensitivity to nikkomycin Z and caspofungin [8].
• The data presented show that reverse genetics was successfully used to isolate genes involved in nikkomycin production [9].

Chemical compound and disease context of AIDS008670

• Histidine aminotransferase activity in Streptomyces tendae and its correlation with nikkomycin production [10].
• Improvement of nikkomycin production by enhanced copy of sanU and sanV in Streptomyces ansochromogenes and characterization of a novel glutamate mutase encoded by sanU and sanV [11].

Biological context of AIDS008670

• Results of limited toxicology tests suggest that nikkomycin Z was well tolerated at the dosages employed [5].
• Polyoxin D was much more effective than nikkomycin Z in inhibiting cell growth [12].
• A study of the pharmacokinetics in mice showed that nikkomycin Z was rapidly eliminated after intravenous infusion but that absorption after oral administration was sufficiently slow to allow inhibitory levels to persist for more than 2 h [5].
• The entire set of structural genes for nikkomycin synthesis was heterologously expressed in S. lividans TK23 by introducing recombinant cosmids p24/32 and p9/43-2, carrying inserts of about 31 and 27 kb, respectively, overlapping by 15 kb [13].
• A genomic library from Streptomyces tendae raised in shuttle cosmid vector pKC505 was screened with a previously isolated 8-kb DNA fragment containing the orfP1 gene, which is involved in nikkomycin biosynthesis [13].

Anatomical context of AIDS008670

• A study of N- and P-dependence of nikkomycin production in continuous culture with immobilized cells [14].
• Incorporation of polysaccharides into the walls of regenerating protoplasts of Candida albicans was followed in the presence of papulacandin B, tunicamycin and nikkomycin [15].

Associations of AIDS008670 with other chemical compounds

• In vitro antifungal activity of nikkomycin Z in combination with fluconazole or itraconazole [16].
• Fungal burden assessed on survivors showed similar levels of Histoplasma antigen in lung and spleen homogenates of mice treated with amphotericin B at 2.0 mg/kg/dose QOD; itraconazole at 75 mg/kg/dose BID; and nikkomycin Z at 100, 20, and 5 mg/kg/dose BID [17].
• The interaction between inhibitors of components of the fungal cell wall, glucan and chitin, was studied in vitro with the respective synthase enzyme inhibitors LY 303366 and nikkomycin Z [18].
• Our results identified the nikC-encoded L-lysine 2-aminotransferase as the nikkomycin biosynthetic enzyme that catalyzes the initial reaction in nikkomycin D biosynthesis [19].
• Furthermore, the nikkomycin-negative phenotype was reversed by the addition of picolinic acid, a precursor of the peptidyl moiety of nikkomycins (nikkomycin D), into the culture medium [19].

Gene context of AIDS008670

• Assays of chitin synthase isozymes and growth assays with isozyme mutants were used to demonstrate that nikkomycin Z is a selective inhibitor of chitin synthase 3 [20].
• Polyoxin D, nikkomycin X, and nikkomycin Z are all competitive inhibitors of chitin synthetase 2 (Chs2), the essential enzyme for primary septum formation in Saccharomyces cerevisiae, and of Chs1, a repair enzyme [12].
• Consistently with a role of chitin in strengthening the cell wall, Phr1- cells are more sensitive to nikkomycin Z than the parental strain [21].
• Feeding larvae of the insect Lucilia cuprina on the fungal chitin synthase competitive inhibitor, nikkomycin Z resulted in strong concentration-dependent mortality of the larvae (LD50 = 280 nM) [22].
• The gene (nikC) encoding protein P8 was cloned from the Streptomyces tendae Tü901 nikkomycin gene cluster and sequenced [19].

Analytical, diagnostic and therapeutic context of AIDS008670

• Expression of genes involved in nikkomycin production in Streptomyces tendae was investigated by two-dimensional gel electrophoresis of cellular proteins [9].
• When administered in doses as low as 2.5 mg/kg twice daily, nikkomycin Z reduced fungal counts in both the spleen and liver [4].
• The echinocandin resistance and the nikkomycin Z supersensitivity of MS14 cosegregated in genetic crosses [23].
• Additionally, by transmission electron microscopy, nikkomycin Z was highly disruptive to the cell wall and internal structure of the spherule-endospore phase of C. immitis in vitro [5].
• The HPLC profile of fermentation products in culture broths of a non-producing mutant, Nik 15, was compared with nikkomycin standards [24].

References