Difficidin and oxydifficidin: novel broad spectrum antibacterial antibiotics produced by Bacillus subtilis. J Antibiot

Merck Sharp and Dohme Research Laboratories, Rahway, New Jersey.
The Journal of Antibiotics (Impact Factor: 1.73). 01/1988; 40(12):1677-81. DOI: 10.7164/antibiotics.40.1677
Source: PubMed


Difficidin and oxydifficidin, two novel macrocyclic polyene lactone phosphate esters were discovered in fermentation broths of each of two strains of Bacillus subtilis: ATCC 39320 and ATCC 39374. Difficidin and oxydifficidin each showed a broad spectrum of activity against aerobic and anaerobic bacteria. Many of the susceptible aerobes and anaerobes were human pathogens resistant to one or more antibiotics. Difficidin and oxydifficidin when administered intraperitoneally protected mice against an otherwise lethal bacteremia caused by Klebsiella pneumoniae (ED50 in mg/kg of 1.31 and 15.6 respectively). Neither difficidin nor oxydifficidin were effective when administered via the subcutaneous route.

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    • "It is also possible that the broad-spectrum antibacterial activity observed was due to a production of the polyketides difficidin , bacillaene, macrolactin and/or the dipeptide bacilysin as the strains I8, A4 and G3 are potentially able to produce these compounds as detected by PCR. Indeed, the polyketide difficidin which is a macrocyclic polyene lactone phosphate ester was shown to have antibacterial effect against S. aureus, Clostridium perfringens, Clostridium difficile , S. Thyphimurium, E. coli and others (Zimmerman et al. 1986), while bacillaene has been reported to be bacteriostatic against, for example B. thuringiensis, E. coli and S. aureus (Patel et al. 1995). "
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    ABSTRACT: To identify and screen dominant Bacillus spp. strains isolated from Bikalga, fermented seeds of Hibiscus sabdariffa for their antimicrobial activities in brain heart infusion (BHI) medium and in a H. sabdariffa seed-based medium. Further, to characterize the antimicrobial substances produced. The strains were identified by gyrB gene sequencing and phenotypic tests as B. amyloliquefaciens ssp. plantarum. Their antimicrobial activity was determined by the agar spot and well assay, being inhibitory to a wide range of Gram-positive and Gram-negative pathogenic bacteria and fungi. Antimicrobial activity against Bacillus cereus was produced in H. sabdariffa seed-based medium. PCR results revealed that the isolates have potential for the lipopeptides iturin, fengycin, surfactin, the polyketides difficidin, macrolactin, bacillaene and the dipeptide bacilysin production. Ultra-high-performance liquid chromatography-time of flight mass spectrometry analysis of antimicrobial substance produced in BHI broth allowed identification of iturin, fengycin and surfactin. The Bacillus amyloliquefaciens ssp. plantarum exhibited broad-spectrum antifungal and antibacterial properties. They produced several lipopeptide antibiotics and showed good potential for biological control of Bikalga. Pathogenic bacteria often occur in spontaneous food fermentations. This is the first report to identify indigenous B. amyloliquefaciens ssp. plantarum strains as potential protective starter cultures for safeguarding Bikalga.
    Journal of Applied Microbiology 04/2013; 115(1). DOI:10.1111/jam.12214 · 2.48 Impact Factor
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    • "The cluster is without counterpart in the genome of Bacillus subtilis 168, however the compounds were first detected in culture broths of two other B. subtilis strains. The polyketides are highly unsaturated 22- membered macrocylic polyene lactone phosphate esters (Wilson et al., 1987) with broad spectrum antibacterial activity (Zimmerman et al., 1987). Difficidin has been shown to inhibit protein biosynthesis (Zweerink and Edison, 1987), but the exact molecular target remains unknown. "
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    ABSTRACT: The genome of plant-associated Bacillus amyloliquefaciens FZB42 harbors an array of giant gene clusters involved in synthesis of lipopeptides and polyketides with antifungal, antibacterial and nematocidal activity. Five gene clusters, srf, bmy, fen, nrs, dhb, covering altogether 137 kb, were shown to direct synthesis of the cyclic lipopeptides surfactin, bacillomycin, fengycin, an unknown peptide, and the iron-siderophore bacillibactin. In addition, one gene cluster encoding enzymes involved in synthesis and export of the antibacterial dipeptide bacilysin is also functional in FZB42. Three gene clusters, mln, bae, and dfn, with a total size of 199 kb were shown to direct synthesis of the antibacterial acting polyketides macrolactin, bacillaene, and difficidin. In total, FZB42 dedicates about 340 kb, corresponding to 8.5% of its total genetic capacity, to synthesis of secondary metabolites. On the contrary, genes involved in ribosome-dependent synthesis of lantibiotics and other peptides are scarce. Apart from two incomplete gene clusters directing immunity against mersacidin and subtilin, only one peptide-like compound has been detected in the culture fluid that inhibits the growth of B. subtilis lacking the alternative sigma factor W.
    Journal of Biotechnology 12/2008; 140(1-2):27-37. DOI:10.1016/j.jbiotec.2008.10.011 · 2.87 Impact Factor
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    ABSTRACT: The nucleotide (nt) sequence of 13.6 kb of the outG locus of Bacillus subtilis, which maps at approximately 155 degrees between the genetic markers nrdA and polC, was determined. One putative coding sequence was identified corresponding to a large polypeptide of 4427 amino acids (aa). Structural organization at the nt and aa sequence level and extensive similarities of the deduced product, especially to EryA, suggest that the locus is potentially responsible for the synthesis of a polyketide molecule. The locus has been renamed pksX. Comparison of the deduced product with known fatty acid and polyketide synthases (PKS) suggested the presence of beta-ketosynthase, dehydratase, beta-ketoreductase and acyl-carrier protein domains. Preliminary data obtained with deletion mutants indicate that pksX is not an essential gene.
    Gene 09/1993; 130(1):65-71. DOI:10.1016/0378-1119(93)90347-6 · 2.14 Impact Factor
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