New nikkomycins by mutasynthesis and directed fermentation.

Delzer, Jürgen; Fiedler, Hans‐Peter; Müller, Hartwig; Zähner, Hans; Rathmann, R.; Ernst, Karin; König, Wilfried Α.

doi:10.7164/antibiotics.37.80

Cited by 46 publications

(14 citation statements)

References 6 publications

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“…In the present study, NZ was found to have the same effect, with inhibition of progressive cleavage and lysis of cells evident. Interestingly, the MIC of the nikkomycins for C. immitis is approximately equal to the calculated Ki value for this agent against the chitin synthase enzyme isolated from diverse fungi (3,10,15,22,23).…”

Section: Discussionmentioning

confidence: 99%

“…The results of intravenous administration indicated that after the initial concentration in serum of 320 ,ug/ml the compound was rapidly eliminated, with a half-life of approximately 10 to 15 min. Results from oral administration with 100 mg/kg, however, suggest that the compound is 10 animals from each group were bled and necropsied. Routine blood counts and chemistry panels (the latter done on pools of three mice each for sufficient volume) revealed no differences among treated groups and untreated controls.…”

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confidence: 99%

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Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis

Hector

Zimmer

Pappagianis

1990

Antimicrob Agents Chemother

177

120

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Nikkomycins X and Z, competitive inhibitors of fungal chitin synthase, were evaluated as therapeutic agents in vitro and in mouse models of coccidioidomycosis, histoplasmosis, and blastomycosis. In vitro, the nikkomycins were found to be most effective against the highly chitinous, dimorphic fungi Coccidioides immitis and Blastomyces dermatitidis, were less effective against yeasts, and were virtually without effect on the filamentous fungus Aspergillus fumigatus. 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. 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. 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. Results of limited toxicology tests suggest that nikkomycin Z was well tolerated at the dosages employed.Several antifungal compounds in use today affect the integrity of the fungal cytoplasmic membrane or the synthesis of its constituent ergosterol. Although some of these drugs have demonstrable efficacies and have been widely utilized for treatment of human patients and animals, there is a clear need for drugs with greater fungicidal activities. Because the cell walls of most medically important fungi contain chitin, a polymer not encountered in mammals, compounds which interfere with the synthesis or degradation of this polymer could be useful in therapy of mycoses (3). The polyoxins, which are specific inhibitors of fungal chitin synthase due to their similarity in structure to UDP-N-acetylglucosamine (reviewed in references 4 and 13), the substrate of chitin synthase, had previously been used in vitro against Candida spp. (1, 22, 31) and dimorphic fungi with some success (6,17). A related group of compounds is the nikkomycins, which are structurally similar to the polyoxins and are also inhibitors of chitin synthase (3, 7). We employed nikkomycins X and Z (NX and NZ, respectively) in vitro against selected medically important fungi representing true yeast, dimorphic, and filamentous groups. Because of the high level of activity of these agents against the dimorphic pathogenic fungi, we subsequently evaluated them in mouse models of coccidioidomycosis, blastomycosis, and histoplasmosis, and the results are reported herein. In addition, data are provided on the pharmacokinetics and safety of these compounds.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis

Hector

Zimmer

Pappagianis

1990

Antimicrob Agents Chemother

177

120

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“…New nikkomycins have been found and isolated by using a photodiode array detector (Fiedler 1984) or mutation techniques (Delzer et al 1984;Bormann et al 1985). For many years it has been known that the strain Streptornyces tendae is able to produce juglomycins as well, Offprint requests to: D. Hege-Treskatis another group of antibiotics very different from nikkomycins (Langh~irig 1978;Werner 1982).…”

Section: Introductionmentioning

confidence: 99%

Nutritional control of nikkomycin and juglomycin production by Streptomyces tendae in continuous culture

Hege-Treskatis

King

Wolf

et al. 1992

Appl Microbiol Biotechnol

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Continuous cultures with Streptomyces tendae revealed some interesting facts. In a continuous culture running for more than 2500 h the production of either nikkomycines or juglomycins could be selected by varying the feed composition. Decreasing the phosphate supply in the feed broth from the initial concentration of 2.5 mM to 1.0 mM enhanced the productivity of nikkomycins and decreased the productivity of juglomycins. When switching back to the initial conditions of the experiment after 2000 h nearly the same production behaviour as at the beginning of the fermentation could be observed. This indicated a stable behaviour of the population with regard to nikkomycin productivity. The long continuous fermentation showed the ability of S. tendae Tü 901/8c to produce nikkomycin at a high level for at least 1500 h. In a second continuous culture it was shown that the productivity of the nikkomycins and juglomycins decreased and increased, respectively, with increasing dilution rate. Comparing batch cultures with continuous fermentations, higher juglomycin productivity was found in the latter. These facts indicate that the strain responds to complex interacting physiological controls, by producing either nikkomycins or juglomycins in a higher amount.

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“…Nikkomycins (Figure 1) are peptidyl nucleoside antibiotics produced by S. ansochromogenes or S. tendae [10,11]. The peptidyl moiety of nikkomycin is hydroxypyridylhomothreonine; while its nucleoside moiety is 5-aminohexuronic acid N -glycosidically bounded uracil in nikkomycin Z (the same as polyoxin K, L and M) or 5-aminohexuronic acid N -glycosidically bounded imidazolone in nikkomycin X.…”

Section: Introductionmentioning

confidence: 99%

Novel polyoxins generated by heterologously expressing polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes

Chen

et al. 2012

Microb Cell Fact

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BackgroundPolyoxins are potent inhibitors of chitin synthetases in fungi and insects. The gene cluster responsible for biosynthesis of polyoxins has been cloned and sequenced from Streptomyces cacaoi and tens of polyoxin analogs have been identified already.ResultsThe polyoxin biosynthetic gene cluster from Streptomyces cacaoi was heterologously expressed in the sanN inactivated mutant of Streptomyces ansochromogenes as a nikkomycin producer. Besides hybrid antibiotics (polynik A and polyoxin N) and some known polyoxins, two novel polyoxin analogs were accumulated. One of them is polyoxin P that has 5-aminohexuronic acid with N-glycosidically bound thymine as the nucleoside moiety and dehydroxyl-carbamoylpolyoxic acid as the peptidyl moiety. The other analog is polyoxin O that contains 5-aminohexuronic acid bound thymine as the nucleoside moiety, but recruits polyoximic acid as the sole peptidyl moiety. Bioassay against phytopathogenic fungi showed that polyoxin P displayed comparatively strong inhibitory activity, whereas the inhibitory activity of polyoxin O was weak under the same testing conditions.ConclusionTwo novel polyoxin analogs (polyoxin P and O) were generated by the heterologous expression of polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes. Polyoxin P showed potent antifungal activity,while the activity of polyoxin O was weak. The strategy presented here may be available for other antibiotics producers.

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New nikkomycins by mutasynthesis and directed fermentation.

Cited by 46 publications

References 6 publications

Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis

Evaluation of nikkomycins X and Z in murine models of coccidioidomycosis, histoplasmosis, and blastomycosis

Nutritional control of nikkomycin and juglomycin production by Streptomyces tendae in continuous culture

Novel polyoxins generated by heterologously expressing polyoxin biosynthetic gene cluster in the sanN inactivated mutant of Streptomyces ansochromogenes

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