Method for efficient and highly selective control of...

Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus

Reexamination Certificate

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C435S006120, C435S254110

Reexamination Certificate

active

06440409

ABSTRACT:

BACKGROUND OF THE INVENTION
Microbial pathogens greatly reduce yields of a variety of important food crops (e.g., corn, rice), threaten entire industries (e.g., rubber, tobacco), and devastate ornamental plants and trees (e.g., elm, chestnut, ash). Unfortunately, treatment with broad-spectrum antimicrobial agents destroys, in addition to the pathogen, important commensal or non-pathogenic organisms and, thus, can facilitate the subsequent colonization by additional pathogens. Therefore, the ideal antimicrobial treatment or therapy is a substance that selectively kills or eliminates specific pathogenic organisms while having minimal effects on the microbial ecology. The importance of the microbial ecology is well-illustrated in the successful use of “antagonistic yeasts,” such as
Epicoccum nigrum, Penicillium oxalicum
, and
Candida sake
, in the control of brown rot of peaches and other fruit. In these examples, protection is a result of the ability of the applied fungal strains to rapidly colonize the fruit and prevent subsequent colonization by organisms associated with post-harvest decay. While these antagonistic approaches can serve as prophylactic treatments, they are much less effective displacing or selectively killing pathogenic or undesirable microorganisms once colonization has occurred.
Selective killing of a microorganism can be achieved by development of a substance that is either selectively toxic or one that is generally toxic but selectively targeted. Development of either type of antimicrobial agent is plagued by the inherent similarities between pathogenic and non-pathogenic organisms at the level of physiology, nutrient requirements, and biology.
Virtually all organisms mate or fuse to allow exchange of genetic and/or other intracellular components. In fungi, fusion is not a random event, but rather is restricted to occur only between members of the same species, and often includes a further dependency on secondary characteristics such as mating type and vegetative compatibility group (VCG). For instance, haploid strains of
S. cerevisiae
will mate and fuse only if they are of opposite mating types. In addition to mating, many filamentous fungi are also able to undergo anastomosis (hyphal fusion) but only if they are of the same vegetative compatibility group. Importantly, these fusion reactions occur with absolute selectivity.
SUMMARY OF THE INVENTION
We have harnessed the biological discriminatory mechanisms described above to selectively target and kill pathogens.
Accordingly, in a first aspect, the invention features a method of selectively killing a first microorganism. The method includes: (i) contacting the first microorganism with a second microorganism that contains a microcidal compound; and (ii) allowing the first microorganism and the second microorganism to undergo fusion, whereby the microcidal compound is delivered into and kills the microorganism that forms following the fusion.
In a preferred embodiment, the first microorganism is fungus. Preferred fungi include Absidia spp.,
Actinomadura madurae
, Actinomyces spp.,
Allescheria boydii
, Altemaria spp.,
Anthopsis deltoidea
, Aphanomyces spp.,
Apophysomyces eleqans
, Armillaria spp.,
Arnium leoporinum
, Aspergillus spp., Aureobasidium pullulans,
Basidiobolus ranarum
, Bipolaris spp.,
Blastomyces dermatitidis
, Botrytis spp., Candida spp., Centrospora spp., Cephalosporium spp., Ceratocystis spp., Chaetoconidium spp., Chaetomium spp., Cladosporium spp.,
Coccidioides immitis
, Colletotrichum spp, Conidiobolus spp.,
Corynebacterium tenuis
, Cryptoporiopsis spp., Cylindrocladium spp., Cryptococcus spp.,
Cunninghamella bertholletiae
, Curvularia spp., Dactylaria spp., Diplodia spp., Epidermophyton spp.,
Epidermophyton floccosum
, Exserophilum spp., Exophiala spp., Fonsecaea spp., Fulvia spp., Fusarium spp., Geotrichum spp., Guignardia spp., Helminthosporium spp., Histoplasma spp., Lecythophora spp., Macrophomina spp., Madurella spp., Magnaporthe spp., Malasseziafurfur, Microsporum spp., Monilinia spp., Mucor spp.,
Mycocentrospora acerina
, Nectria spp., Nocardia spp., Oospora spp., Ophiobolus spp., Paecilomyces spp.,
Paracoccidioides brasiliensis
, Penicillium spp.,
Phaeosclera dematioides
, Phaeoannellomyces spp., Phialemonium obovatum, Phialophora spp., Phlyctaena spp., Phoma spp., Phomopsis spp., Phymatotrichum spp., Phytophthora spp., Pythium spp.,
Piedraia hortai, Pneumocystis carinii
, Puccinia spp.,
Pythium insidiosum, Rhinocladiella aquaspersa, Rhizomucor pusillus
, Rhizoctonia spp., Rhizopus spp., Saccharomyces spp.,
Saksenaea vasiformis, Sarcinomyces phaeomuriformis
, Scerotium spp., Sclerotinia spp., Sphaerotheca spp.,
Sporothrix schenckii, Syncephalastrum racemosum, Taeniolella boppii
, Taphrina spp., Thielaviopsis spp., Torulopsosis spp., Trichophyton spp., Trichosporon spp.,
Ulocladium chartarum
, Ustilago spp., Venturia spp., Verticillium spp.,
Wangiella dermatitidis
, Whetxelinia spp., Xylohypha spp., and their synonyms.
In another preferred embodiment, the compound is a toxic compound or is a compound that causes a toxic compound to be produced in the microorganism that forms following fusion. Preferably, the toxic compound is a toxin or fragment thereof selected from the group consisting of: diphtheria toxin, diphtheria toxin F2 fragment, diphtheria toxin A domain, Pseudomonas exotoxin A, and the A domain of Pseudomonas exotoxin A. Alternatively, the compound is a biosynthetic enzyme that causes a toxic compound to be produced in the microorganism that forms following fusion.
In a related embodiment, the second microorganism is resistant to the microcidal compound. In preferred embodiments, the second microorganism is a nonpathogenic fungus.
In a second aspect, the invention features a method for producing a diphtheria toxin-resistant fungus. The method includes introducing into the fungus a mutation in its DPH1, DPH3, or DPH4 gene that prevents the biosynthesis of diphthamide, wherein the fungus is selected from the group consisting of: Absidia spp.,
Actinomadura madurae
, Actinomyces spp.,
Allescheria boydii
, Altemaria spp., Anthopsis deltoidea, Aphanomyces spp.,
Apophysomyces eleqans
, Armillaria spp.,
Arnium leoporinum
, Aspergillus spp.,
Aureobasidium pullulans, Basidiobolus ranarum
, Bipolaris spp.,
Blastomyces dermatitidis
, Botrytis spp., Candida spp., Centrospora spp., Cephalosporium spp., Ceratocystis spp., Chaetoconidium spp., Chaetomium spp., Cladosporium spp.,
Coccidioides immitis
, Colletotrichum spp, Conidiobolus spp.,
Corynebacterium tenuis
, Cryptoporiopsis spp., Cylindrocladium spp., Cryptococcus spp.,
Cunninghamella bertholletiae
, Curvularia spp., Dactylaria spp., Diplodia spp., Epidermophyton spp.,
Epidermophyton floccosum
, Exserophilum spp., Exophiala spp., Fonsecaea spp., Fulvia spp., Fusarium spp., Geotrichum spp., Guignardia spp., Helminthosporium spp., Histoplasma spp., Lecythophora spp., Macrophomina spp., Madurella spp., Magnaporthe spp.,
Malassezia furfur
, Microsporum spp., Monilinia spp., Mucor spp.,
Mycocentrospora acerina
, Nectria spp., Nocardia spp., Oospora spp., Ophiobolus spp., Paecilomyces spp.,
Paracoccidioides brasiliensis
, Penicillium spp.,
Phaeosclera dematioides
, Phaeoannellomyces spp.,
Phialemonium obovatum
, Phialophora spp., Phlyctaena spp., Phoma spp., Phomopsis spp., Phymatotrichum spp., Phytophthora spp., Pythium spp.,
Piedraia hortai, Pneumocystis carinii
, Puccinia spp.,
Pythium insidiosum, Rhinocladiella aquaspersa, Rhizomucor pusillus
, Rhizoctonia spp., Rhizopus spp., Saccharomyces spp.,
Saksenaea vasiformis, Sarcinomyces phaeomuriformnis
, Scerotium spp., Sclerotinia spp., Sphaerotheca spp.,
Sporothrix schenckii, Syncephalastrum racemosum, Taeniolella boppii
, Taphrina spp., Thielaviopsis spp., Torulopsosis spp., Trichophyton spp., Trichosporon spp.,
Ulocladium chartarum
, Ustilago spp., Venturia spp., Verticillium spp.,
Wangiella dermatitidis
, Whetxelinia spp., and Xylohypha spp.
In a third aspect, the invention features a diphtheria toxin-resistant fungus containing a mutation

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