BISMUTH-THIOLS AS ANTISEPTICS FOR AGRICULTURAL, INDUSTRIAL AND OTHER USES

• US 20130224258A1
• Filed: 02/12/2013
• Published: 08/29/2013
• Est. Priority Date: 02/03/2010
• Status: Active Grant

• Current Assignee: Microbion Corporation
• Original Assignee: Microbion Corporation
• Inventors: Baker, Brett Hugh James
• Granted Patent: US 9,408,393 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A01N 25/08 containing solids as carriers or diluents
• CPC Class Codes: A01N 37/18 containing the group —CO—N<, e.g. carboxylic acid amides or imides; Thio analogues thereof
• CPC Class Codes: A01N 43/16 with oxygen as the ring hetero atom
• CPC Class Codes: A01N 43/36 five-membered rings
• CPC Class Codes: A01N 43/40 six-membered rings
• CPC Class Codes: A01N 43/54 1,3-Diazines; Hydrogenated 1,3-diazines
• CPC Class Codes: A01N 43/60 1,4-Diazines; Hydrogenated 1,4-diazines
• CPC Class Codes: A01N 43/78 1,3-Thiazoles; Hydrogenated 1,3-thiazoles
• CPC Class Codes: A01N 43/84 six-membered rings with one nitrogen atom and either one oxygen atom or one sulfur atom in positions 1,4
• CPC Class Codes: A01N 43/90 having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
• CPC Class Codes: A01N 45/00 Biocides, pest repellants or attractants, or plant growth regulators, containing compounds having three or more carbocyclic rings condensed among themselves, at least one ring not being a six-membered ring halogenated hydrocarbons A01N29/08; condensed with heterocyclic rings A01N43/00
• CPC Class Codes: A01N 47/44 Guanidine; Derivatives thereof
• CPC Class Codes: A01N 55/02 containing metal atoms
• CPC Class Codes: A01N 57/24 containing heterocyclic radicals
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/431 containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/4409 only substituted in position 4, e.g. isoniazid, iproniazid
• CPC Class Codes: A61K 31/496 Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
• CPC Class Codes: A61K 31/5377 : not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 31/5383 : ortho- or peri-condensed with heterocyclic ring systems
• CPC Class Codes: A61K 31/546 : containing further heterocyclic rings, e.g. cephalothin
• CPC Class Codes: A61K 31/555 : containing heavy metals, e.g. hemin, hematin, melarsoprol
• CPC Class Codes: A61K 31/65 : Tetracyclines
• CPC Class Codes: A61K 31/665 : having oxygen as a ring hetero atom, e.g. fosfomycin
• CPC Class Codes: A61K 31/7028 : Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
• CPC Class Codes: A61K 31/7036 : having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
• CPC Class Codes: A61K 31/7048 : having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61K 38/12 : Cyclic peptides , e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C A61K38/043 - A61K38/046 take precedence
• CPC Class Codes: A61K 38/14 : Peptides containing saccharide radicals; Derivatives thereof , e.g. bleomycin, phleomycin, muramylpeptides or vancomycin
• CPC Class Codes: A61K 9/0014 : Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61K 9/06 : Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels composition of ointments, creams or gels A61K47/00
• CPC Class Codes: A61K 9/10 : Dispersions; Emulsions A61K9/06 takes precedence; composition of dispersions, emulsions A61K47/00
• CPC Class Codes: A61K 9/16 : Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction A61K9/20 takes precedence if the final form is a tablet; microspheres with drug-free outer coating, microcapsules A61K9/50; mixture of different granules, microcapsules, (coated) microparticles A61K9/5084; nanoparticles A61K9/51
• CPC Class Codes: A61K 9/7023 : Transdermal patches and similar drug-containing composite devices, e.g. cataplasms galenical aspects of iontophoretic devices A61K9/0009; microneedle arrays A61K9/0021; buccal patches A61K9/006
• CPC Class Codes: A61L 2300/404 : Biocides, antimicrobial agents, antiseptic agents
• CPC Class Codes: A61L 24/0015 : Medicaments; Biocides
• CPC Class Codes: A61L 24/0031 : Hydrogels or hydrocolloids
• CPC Class Codes: A61L 24/06 : obtained by reactions only involving carbon-to-carbon unsaturated bonds A61L24/043, A61L24/046 take precedence
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Compositions and methods, including novel homogeneous microparticulate suspensions, are described for treating natural and artificial surfaces that contain bacterial biofilm, including unexpected synergy or enhancing effects between bismuth-thiol (BT) compounds and certain antibiotics, to provide formulations including antiseptic formulations. Previously unpredicted antibacterial properties and anti-biofilm properties of disclosed BT compounds and BT compound-plus-antibiotic combinations are also described, including preferential efficacies of certain such compositions for treating certain gram-positive bacterial infections, and distinct preferential efficacies of certain such compositions for treating certain gram-negative bacterial infections.

Claims

1. A method for protecting a plant against a bacterial, fungal or viral pathogen, comprising:

contacting the plant with an effective amount of a bismuth-thiol (BT) composition under conditions and for a time sufficient for one or more of;

(i) prevention of infection of the plant by the bacterial, fungal or viral pathogen,

(ii) inhibition of cell viability or cell growth of substantially all planktonic cells of the bacterial, fungal or viral pathogen,

(iii) inhibition of biofilm formation by the bacterial, fungal or viral pathogen, and

(iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the bacterial, fungal or viral pathogen,

wherein the BT composition comprises a substantially monodisperse suspension of microparticles that comprise a BT compound, said microparticles having a volumetric mean diameter of from about 0.4 μ

m to about 10 μ

m.

2. The method of claim 1 wherein the bacterial pathogen comprises Erwinia amylovora cells.

3. The method of claim 1 wherein the bacterial pathogen is selected from the group consisting of Erwinia amylovora, Xanthomonas campestris pv dieffenbachiae, Pseudomonas syringae, Xylella fastidiosa;

Xylophylus ampelinus;

Monilinia fructicola, Pantoea stewartii subsp. Stewartii, Ralstonia solanacearum, and Clavibacter michiganensis subsp. sepedonicus.

4. The method of claim 1 wherein the bacterial pathogen exhibits antibiotic resistance.

5. The method of claim 1 wherein the bacterial pathogen exhibits streptomycin resistance.

6. The method of claim 1 wherein the plant is a food crop plant.

7. The method of claim 6 wherein the food crop plant is a fruit tree.

8. The method of claim 7 wherein the fruit tree is selected from the group consisting of an apple tree, a pear tree, a peach tree, a nectarine tree, a plum tree, an apricot tree.

9. The method of claim 6 wherein the food crop plant is a banana tree of genus Musa.

10. The method of claim 6 wherein the food crop plant is a plant selected from a tuberous plant, a leguminous plant, and a cereal grain plant.

11. The method of claim 10 wherein the tuberous plant is selected from the group consisting of Solanum tuberosum (potato), and Ipomoea batatas (sweet potato).

12. The method of claim 1 in which the step of contacting is performed one or a plurality of times.

13. The method of claim 12 in which at least one step of contacting comprises one of spraying, dipping, coating and painting the plant.

14. The method of claim 12 in which at least one step of contacting is performed at a flower blossom, green-tip or growth site of the plant.

15. The method of claim 12 in which at least one step of contacting is performed within 24, 48 or 72 hours of first flower blooming on the plant.

16. The method of claim 1 wherein the BT composition comprises one or more BT compounds selected from the group consisting of BisBAL, BisEDT, Bis-dimercaprol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-mercapto-2-propanol, and Bis-EDT/2-hydroxy-1-propanethiol.

17. The method of claim 1 wherein the bacterial pathogen exhibits antibiotic resistance.

18. The method of claim 1 which further comprises contacting the plant with a synergizing or enhancing antibiotic, simultaneously or sequentially and in any order with respect to the step of contacting the plant with the BT composition.

19. The method of claim 18 wherein the synergizing or enhancing antibiotic comprises an antibiotic that is selected from the group consisting of an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic.

20. The method of claim 19 wherein the synergizing or enhancing antibiotic is an aminoglycoside antibiotic that is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin.

22. The method of claim 1 wherein the bismuth-thiol composition comprises a plurality of microparticles that comprise a bismuth-thiol (BT) compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μ

m to about 5 μ

m and being formed by a process that comprises;

(a) admixing, under conditions and for a time sufficient to obtain a solution that is substantially free of a solid precipitate, (i) an acidic aqueous solution that comprises a bismuth salt comprising bismuth at a concentration of at least 50 mM and that lacks a hydrophilic, polar or organic solubilizer, with (ii) ethanol in an amount sufficient to obtain an admixture that comprises about 25% ethanol by volume; and

(b) adding to the admixture of (a) an ethanolic solution comprising a thiol-containing compound to obtain a reaction solution, wherein the thiol-containing compound is present in the reaction solution at a molar ratio of from about 1;

3 to about 3;

1 relative to the bismuth, under conditions and for a time sufficient for formation of a precipitate which comprises the microparticles comprising the BT compound.

23. The method of claim 22 wherein the bismuth salt is Bi(NO₃)₃.

24. The method of claim 22 wherein the acidic aqueous solution comprises at least 5%, 10%, 15%, 20%, 22% or 22.5% bismuth by weight.

25. The method of claim 22 wherein the acidic aqueous solution comprises at least 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% or 5% nitric acid by weight.

26. The method of claim 22 wherein the thiol-containing compound comprises one or more agents selected from the group consisting of 1,2-ethane dithiol, 2,3-dimercaptopropanol, pyrithione, dithioerythritol, 3,4-dimercaptotoluene, 2,3-butanedithiol, 1,3-propanedithiol, 2-hydroxypropane thiol, 1-mercapto-2-propanol, dithioerythritol, alpha-lipoic acid, dithiothreitol, methanethiol (CH₃SH [m-mercaptan]), ethanethiol (C₂H₅SH [e-mercaptan]), 1-propanethiol (C₃H₇SH [n-P mercaptan]), 2-propanethiol (CH₃CH(SH)CH_{3 [}2C₃ mercaptan]), butanethiol (C₄H₉SH ([n-butyl mercaptan]), tert-butyl mercaptan (C(CH₃)₃SH [t-butyl mercaptan]), pentanethiol (C₅H₁₁SH [pentyl mercaptan]), coenzyme A, lipoamide, glutathione, cysteine, cystine, 2-mercaptoethanol, dithiothreitol, dithioerythritol, 2-mercaptoindole, transglutaminase, (11-mercaptoundecyl)hexa(ethylene glycol), (11-mercaptoundecyl)tetra(ethylene glycol), (11-mercaptoundecyl)tetra(ethylene glycol) functionalized gold nanoparticles, 1,1′

,4′

,1″

-terphenyl-4-thiol, 1,11-undecanedithiol, 1,16-hexadecanedithiol, 1,2-ethanedithiol technical grade, 1,3-propanedithiol, 1,4-benzenedimethanethiol, 1,4-butanedithiol, 1,4-butanedithiol diacetate, 1,5-pentanedithiol, 1,6-hexanedithiol, 1,8-octanedithiol, 1,9-nonanedithiol, adamantanethiol, 1-butanethiol, 1-decanethiol, 1-dodecanethiol, 1-heptanethiol, 1-heptanethiol purum, 1-hexadecanethiol, 1-hexanethiol, 1-mercapto-(triethylene glycol), 1-mercapto-(triethylene glycol) methyl ether functionalized gold nanoparticles, 1-mercapto-2-propanol, 1-nonanethiol, 1-octadecanethiol, 1-octanethiol, 1-octanethiol, 1-pentadecanethiol, 1-pentanethiol, 1-propanethiol, 1-tetradecanethiol, 1-tetradecanethiol purum, 1-undecanethiol, 11-(1H-pyrrol-1-yl)undecane-1-thiol, 11-amino-1-undecanethiol hydrochloride, 11-bromo-1-undecanethiol, 11-mercapto-1-undecanol, 11-mercapto-1-undecanol, 11-mercaptoundecanoic acid, 11-mercaptoundecanoic acid, 11-mercaptoundecyl trifluoroacetate, 11-mercaptoundecylphosphoric acid, 12-mercaptododecanoic acid, 12-mercaptododecanoic acid, 15-mercaptopentadecanoic acid, 16-mercaptohexadecanoic acid, 16-mercaptohexadecanoic acid, 1H,1H,2H,2H-perfluorodecanethiol, 2,2′

-(ethylenedioxy)diethanethiol, 2,3-butanedithiol, 2-butanethiol, 2-ethylhexanethiol, 2-methyl-1-propanethiol, 2-methyl-2-propanethiol, 2-phenylethanethiol, 3,3,4,4,5,5,6,6,6-nonafluoro-1-hexanethiol purum, 3-(dimethoxymethylsilyl)-1-propanethiol, 3-chloro-1-propanethiol, 3-mercapto-1-propanol, 3-mercapto-2-butanol, 3-mercapto-N-nonylpropionamide, 3-mercaptopropionic acid, 3-mercaptopropyl-functionalized silica gel, 3-methyl-1-butanethiol, 4,4′

-bis(mercaptomethyl)biphenyl, 4,4′

-dimercaptostilbene, 4-(6-mercaptohexyloxy)benzyl alcohol, 4-cyano-1-butanethiol, 4-mercapto-1-butanol, 6-(ferrocenyl)hexanethiol, 6-mercapto-1-hexanol, 6-mercaptohexanoic acid, 8-mercapto-1-octanol, 8-mercaptooctanoic acid, 9-mercapto-1-nonanol, biphenyl-4,4′

-dithiol, butyl 3-mercaptopropionate, copper(I) 1-butanethiolate, cyclohexanethiol, cyclopentanethiol, decanethiol functionalized silver nanoparticles, dodecanethiol functionalized gold nanoparticles, dodecanethiol functionalized silver nanoparticles, hexa(ethylene glycol)mono-11-(acetylthio)undecyl ether, mercaptosuccinic acid, methyl 3-mercaptopropionate, nanoTether BPA-HH, NanoThinks™

18, NanoThinks™

8, NanoThinks™

ACID11, NanoThinks™

ACID16, NanoThinks™

ALCO11, NanoThinks™

THIO8, octanethiol functionalized gold nanoparticles, PEG dithiol average M_n 8,000, PEG dithiol average mol wt 1,500, PEG dithiol average mol wt 3,400, S-(11-bromoundecyl)thioacetate, S-(4-cyanobutyl)thioacetate, thiophenol, triethylene glycol mono-11-mercaptoundecyl ether, trimethylolpropane tris(3-mercaptopropionate), [11-(methylcarbonylthio)undecyl]tetra(ethylene glycol), m-carborane-9-thiol, p-terphenyl-4,4″

-dithiol, tert-dodecylmercaptan, and tert-nonyl mercaptan.

27. The method of claim 1 wherein the bacterial pathogen comprises at least one of:

(i) one or more gram-negative bacteria;

(ii) one or more gram-positive bacteria;

(iii) one or more antibiotic-sensitive bacteria;

(iv) one or more antibiotic-resistant bacteria;

(v) a bacterial pathogen that is selected from the group consisting of Staphylococcus aureus (S. aureus), MRSA (methicillin-resistant S. aureus), Staphylococcus epidermidis, MRSE (methicillin-resistant S. epidermidis), Mycobacterium tuberculosis, Mycobacterium avium, Pseudomonas aeruginosa, drug-resistant P. aeruginosa, Escherichia coli, enterotoxigenic E. coli, enterohemorrhagic E. coli, Klebsiella pneumoniae, Clostridium difficile, Heliobacter pylori, Legionella pneumophila, Enterococcus faecalis, methicillin-susceptible Enterococcus faecalis, Enterobacter cloacae, Salmonella typhimurium, Proteus vulgaris, Yersinia enterocolitica, Vibrio cholera, Shigella flexneri, vancomycin-resistant Enterococcus (VRE), Burkholderia cepacia complex, Francisella tularensis, Bacillus anthracis, Yersinia pestis, Pseudomonas aeruginosa, Streptococcus pneumonia, penicillin-resistant Streptococcus pneumonia, Escherichia coli, Burkholderia cepacia, Bukholderia multivorans, Mycobacterium smegmatis and Acinetobacter baumannii.

28. The method of claim 1 which comprises contacting the plant with at least one of (i) a synergizing antibiotic and (ii) a cooperative antimicrobial efficacy enhancing antibiotic, simultaneously or sequentially and in any order with respect to the step of contacting the surface with the BT composition.

29. The method of claim 28 wherein the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing antibiotic comprises an antibiotic that is selected from the group consisting of an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a glycopeptide antibiotic, a lincosamide antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic.

30. The method of claim 29 wherein the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing antibiotic is an aminoglycoside antibiotic that is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin.

21. A method for overcoming antibiotic resistance in a plant in or on which an antibiotic-resistant bacterial plant pathogen is present, comprising

(a) contacting the plant with an effective amount of a BT composition under conditions and for a time sufficient for one or more of:

(i) prevention of infection of the plant by the antibiotic-resistant bacterial pathogen,

(ii) inhibition of cell viability or cell growth of substantially all planktonic cells of the antibiotic-resistant bacterial pathogen,

(iii) inhibition of biofilm formation by the antibiotic-resistant bacterial pathogen, and

(iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the antibiotic-resistant bacterial pathogen,

wherein the BT composition comprises a substantially monodisperse suspension of microparticles that comprise a BT compound, said microparticles having a volumetric mean diameter of from about 0.5 μ

m to about 10 μ

m; and

(b) contacting the plant with a synergizing or enhancing antibiotic, simultaneously or sequentially and in any order with respect to the step of contacting the plant with the BT composition.

31. A method for overcoming antibiotic resistance in or on a plant where an antibiotic-resistant bacterial pathogen is present, comprising:

contacting the plant simultaneously or sequentially and in any order with an effective amount of (1) at least one bismuth-thiol (BT) composition and (2) at least one antibiotic that is capable of enhancing or acting synergistically with the at least one BT composition, under conditions and for a time sufficient for one or more of;

(i) prevention of infection of the plant by the bacterial pathogen,

(ii) inhibition of cell viability or cell growth of substantially all planktonic cells of the bacterial pathogen,

(iii) inhibition of biofilm formation by the bacterial pathogen, and

(iv) inhibition of biofilm viability or biofilm growth of substantially all biofilm-form cells of the bacterial pathogen,

wherein the BT composition comprises a plurality of microparticles that comprise a bismuth-thiol (BT) compound, substantially all of said microparticles having a volumetric mean diameter of from about 0.4 μ

m to about 5 μ

m; and

thereby overcoming antibiotic resistance on the epithelial tissue surface.

32. The method of claim 31 wherein the bacterial pathogen exhibits resistance to an antibiotic that is selected from the group consisting of methicillin, vancomycin, naficilin, gentamicin, ampicillin, chloramphenicol, doxycycline, tobramycin, clindamicin and gatifloxacin.

33. The method of claim 31 wherein the BT composition comprises one or more BT compounds selected from the group consisting of BisBAL, BisEDT, Bis-dimercaprol, Bis-DTT, Bis-2-mercaptoethanol, Bis-DTE, Bis-Pyr, Bis-Ery, Bis-Tol, Bis-BDT, Bis-PDT, Bis-Pyr/Bal, Bis-Pyr/BDT, Bis-Pyr/EDT, Bis-Pyr/PDT, Bis-Pyr/Tol, Bis-Pyr/Ery, bismuth-1-mercapto-2-propanol, and Bis-EDT/2-hydroxy-1-propanethiol.

34. The method of claim 33 wherein the synergizing or enhancing antibiotic comprises an antibiotic that is selected from the group consisting of clindamicin, gatifloxacin, an aminoglycoside antibiotic, a carbapenem antibiotic, a cephalosporin antibiotic, a fluoroquinolone antibiotic, a penicillinase-resistant penicillin antibiotic, and an aminopenicillin antibiotic.

35. The method of claim 34 wherein the synergizing or enhancing antibiotic is an aminoglycoside antibiotic that is selected from the group consisting of amikacin, arbekacin, gentamicin, kanamycin, neomycin, netilmicin, paromomycin, rhodostreptomycin, streptomycin, tobramycin and apramycin.