Pyrrolnitrin antifungal activity

S. pyrocinia produces [118] an antifungal antibiotic pyrrolnitrin (140) active against mycobacteria. The antimycobacterial activity can be well correlated with the presence of the halogen and nitro group in the aromatic ring. 

New phenyl pyrroles are produced55 vhen certain analogues of tryptophan (dl-6-fluorotryptophan and dl-7-methyltrypto-phan) are added to pyrrolnitrin-producing cultures. The new compounds, it -fluoropyrrolnitrin and 3 > thyl-3 -dechloro-pyrrolnitrin, still possessed significant antifungal activity. The x-ray crystal structures of pyrrolnitrin and -fluoro-pyrrolnitrin have been determined.5° 57... 

Fermentation experiments were undertaken using the complex medium (Table 2) and after cell multiplication was essentially complete (24 hours), the appropriate precursor was added at a level of 500 and lOOOmcg/ml. At the end of 120 hours, the flasks were assayed and the antibiotic isolated. Phenylalanine, anthranilic acid, phenylsuccinic acid and phenylpyrrole either greatly reduced pyrrolnitrin levels or had no observable effect on the fermentation. In contrast, the addition of DL-tr3 tophan increased the level of antifungal activity approximately two-fold (from 44 mcg/ml in the control flasks to 80—94 mcg/ml with tryptophan added). When d- and L-tryptophan were used separately, it was found that 250—500 mcg/ml of the D-isomer produced the two-fold increase in pyrrolnitrin levels. There was no change in the amount of pyrrolnitrin obtained... 

A crude extract obtained from a culture of a soil actinomycete showed activity toward C. elegans. The major active component isolated from this mixture was dioxapyrrolomycin (237) [401], a compound reminiscent of the antifungal metabolites, pyoluteorin and pyrrolnitrin, produced by some Pseudomonads from tryptophan. Recent progress in the biosynthesis of these compounds has been reviewed [402]. Dioxapyrrolomycin (237) was found to be active against H. contortus in the jird model (>91% clearance at 0.33 pg/jird) and in lambs at 12.5 mg/kg (99.9% clearance). 

Compounds related to tr5 tophan were studied for effects on pyrrolnitrin production. The following compounds appeared to lower the amount of antifungal agent produced tryptamine, indole-3-acetic acid, and indole. No effect on the level of biological activity was seen with D,L-serine or shikimic acid. N-chloroacetyl tr5q)tophan enhanced the quantity of metabolite produced, probably by hydrolysis to tryptophan. 

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