Bismuth-thiols as antiseptics for agricultural, industrial and other uses

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.

1 . A method for protecting a natural surface of a mammalian tissue or an artificial surface against a bacterial, fungal or viral pathogen, comprising:
 contacting the natural or artificial surface 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 natural or artificial surface by the bacterial, fungal or viral pathogen,   (ii) inhibition of cell viability or cell growth on the natural or artificial surface of substantially all planktonic cells of the bacterial, fungal or viral pathogen,   (iii) inhibition of biofilm formation on the natural or artificial surface by the bacterial, fungal or viral pathogen, and   (iv) inhibition of biofilm viability or biofilm growth on the natural or artificial surface 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 μm to about 10 μm.   
     
     
         2 - 20 . (canceled) 
     
     
         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 μm to about 10 μm; 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.   
     
     
         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 μm to about 5 μm 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(NO 3 ) 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, ethanethiol, 1-propanethiol, 2-propanethiol, butanethiol, tert-butyl mercaptan, pentanethiol-, 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, 1,4-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-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-pentadecanethiol, 1-pentanethiol, 1-tetradecanethiol, 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, 3-(dimethoxymethyl silyl)-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 natural surface of the mammalian tissue or the artificial surface 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, wherein if the BT compound is bismuth-1,2-ethane dithiol (BisEDT) then the synergizing antibiotic or the cooperative antimicrobial efficacy enhancing antibiotic is not tobramycin, nafcillin, gentamicin, clindamycin, gatifloxacin, minocycline, vancomvcin or cefazolin. 
     
     
         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. 
     
     
         31 . (canceled) 
     
     
         32 . The method of  claim 1  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 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. 
     
     
         34 - 35 . (canceled) 
     
     
         36 . The method of  claim 1  in which an article of manufacture comprises the artificial surface. 
     
     
         37 . The method of  claim 36  wherein the artificial surface comprises one or more of a cement surface, a concrete surface, a rubber surface, a silicone surface, a plastic surface, a painted surface, or a coated surface. 
     
     
         38 . The method of  claim 1  wherein the natural surface of the mammalian tissue or the artificial surface is present (i) at a surgical site, (ii) on a medical device or medical implant, (iii) on a dental device or dental implant, or (iv) on a bone, joint, tendon, muscle, ligament, epithelium or tooth. 
     
     
         39 . The method of  claim 38  wherein the medical device or medical implant is a bone or joint prosthesis; a bone fracture-, fusion-, or osteotomy-stabilizing hardware; a catheter; a stent; a feeding tube or a gastrostomy tube. 
     
     
         40 . The method of  claim 1  wherein the natural surface of the mammalian tissue or the artificial surface comprises one or more of (i) a bone or joint prosthesis or a bone fracture-, fusion-, or osteotomy-stabilizing hardware; and (ii) a tissue or skeletal structure that is adjacent to a bone or joint prosthesis or to a bone fracture-, fusion-, or osteotomy-stabilizing hardware, and wherein the BT composition comprises the BT microparticles in a bone cement. 
     
     
         41 . The method of  claim 40  wherein the bone cement comprises a hydrogel. 
     
     
         42 . The method of  claim 41  wherein the hydrogel comprises polymethylmethacrylate. 
     
     
         43 . The method of  claim 40  wherein the microparticulate BT compound is selected from bismuth-1,2-ethanedithiol (EDT), bismuth-pyrithione/-1,2-ethanedithiol, and bismuth-pyrithione/2,3-butanedithiol. 
     
     
         44 . The method of  claim 1  wherein contacting the natural surface of the mammalian tissue or the artificial surface comprises administering the BT composition to at least one of:
 (a) one or more mammalian tissue that is selected from skin, scalp, epidermis, dermis, cornea, sclera, muscle, teeth, bone, joint, tendon, and ligament, 
 (b) one or more mammalian tissue that is selected from gastrointestinal tract lining, buccal cavity, and a mucous membrane, 
 (c) one or more mammalian tissue that is selected from endothelia, an epithelial tissue surface, an arthroplasty site, a bone fusion site, a respiratory airway, nasopharyngeal tissue, laryngeal tissue, tracheal tissue, pulmonary tissue, bronchi, bronchioles, alveoli, a peritoneal membrane, a pericardial membrane, a pleural membrane, a periosteal membrane, a meningeal membrane, and a sarcolemmal membrane, 
 (d) one or more mammalian tissue that is selected from heart, lung, kidney, liver, spleen, gall bladder, pancreas, bladder, and nerve, 
 (e) one or more of (i) a bone or joint prosthesis or a bone fracture-, fusion-, or osteotomy-stabilizing hardware, (ii) a tissue or skeletal structure that is adjacent to a bone or joint prosthesis or to a bone fracture-, fusion-, or osteotomy-stabilizing hardware, and (iii) a medical implant or graft. 
 
     
     
         45 . The method of  claim 1  which comprises treating one or more of a skin infection, a soft tissue infection, a wound infection, a chronic wound biofilm, a biofilm that is in or on a medical device, and an open fracture.