Methods and compositions for bacteria infections

Abstract

Compositions and methods are provided for treating or inhibiting a bacterial infection involving at least one antibiotic and a compound that potentiates the antibiotic activity of the antibiotic. In certain embodiments the antibiotic is a beta lactam. In further embodiments, the antibiotic is oxacillin. In additional embodiments, the potentiating compound is an inhibitor of vraSR operon expression. In specific embodiments, the bacterial infection involves an antibiotic-resistant bacteria.

1 . A method for inhibiting a  staphylococcus  infection comprising administering to a subject having a  staphylococcus  infection or at risk of a  staphylococcus  infection:
 (a) an antibiotic, and;   (b) an antibiotic potentiator, wherein the antibiotic potentiator is a compound of the formula:   
       
         
           
           
               
               
           
         
         wherein R 1  may be -(4-chlorophenoxy)methyl, 1-(thiophen-2-yl)cyclopentyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 1-isopropyl-1H-pyrazol-5-yl, 2-(thiophen-2-yl)quinolin-4-yl, 2,3-dihyrdobenzo[b] [1,4]dioxin-6-yl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl, 2,6-difluorophenyl, 2-bromothiophen-5-yl, 2-chlorothiophen-5-yl, 2-naphthyl, 2-phenoxyphenyl, 2-phenylquinolin-4-yl, 2-tolyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, 3,4,5-trimethoxyphenyl, 3,5-dichlorophenyl, 3,5-dimethoxyphenyl, 3-bromophenyl, 3-chlorobenzo[b]thiophen-2-yl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-n-butoxyphenyl, 3-phenoxyphenyl, 3-tolyl, 3-trifluoromethylphenyl, 4-(2,6-dimethylmorpholinosulfonyl)phenyl, 4-(2-ethylpiperidin-1-ylsulfonyl)phenyl, 4-(2-methylpiperidin-1-ylsulfonyl)phenyl, 4-(2-phenylquinoline), 4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl, 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl, 4-(3,5-dimethylpiperidin-1-ylsulfonyl)phenyl, 4-(4,4-dimethyloxazolidin-3-ylsulfonyl)phenyl, 4-(morpholinosulfonyl)phenyl, 4-(N,N-diallyl sulfamoyl)phenyl, 4-(N,N-diethyl sulfamoyl)phenyl, 4-(N,N-diisobutylsulfamoyl)phenyl, 4-(N,N-dimethyl sulfamoyl)phenyl, 4-(N-ethyl-N-benzyl sulfamoyl)phenyl, 4-(N-ethyl-N-n-butyl-sulfamoyl)phenyl, 4-(N-ethyl-N-phenyl sulfamoyl)phenyl, 4-(N-isopropyl-N-benzylsulfamoyl)phenyl 4-(N-methyl-N-benzyl sulfamoyl)phenyl, 4-(N-methyl-N-cyclohexyl sulfamoyl)phenyl, 4-(N-methyl-N-n-butyl sulfamoyl)phenyl, 4-(N-methyl-N-phenyl sulfamoyl)phenyl, 4-(piperidin-1-ylsulfonyl)phenyl, 4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-benzoylphenyl, 4-benzylphenyl, 
         4-biphenyl, 4-chlorophenyl, 4-diphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-phenoxyphenyl, 4-tert-butylphenyl, 7-methoxybenzofuran-2-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-6-yl, benzofuran-2-yl, diphenylmethyl, methyl-4-benzoate, phenyl, or thiophen-2-yl, and 
         R 2  may be 1,2,3,4-tetrahydronaphthalen-6-yl, 2-(methylthio)phenyl, 2,3-dihydro-1,4-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-6-yl, 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl 2,5-dimethylphenyl, 2-bromothiophen-2-yl, 2-chlorophenyl, 2-chlorothiophen-2-yl, 2-chlorothiophen-5-yl, 2-furanyl, 2-methoxyphenyl, 2-pyridinyl, 3-(methylthio)phenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-methoxyphenyl, 3-pyridinyl, 4-chlorophenyl, 4-(methylthio)phenyl, 4-bromophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl, 4-pyridinyl, 4-trifluoromethoxyphenyl, 7-ethoxybenzofuran-2-yl, 7-methoxybenzofuran-2-yl, benzofuran-2-yl, benzyl, phenyl, or thiophen-2-yl, or an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
       
       or
 an antibiotic potentiator having the formula: 
 
       
         
           
           
               
               
           
         
         wherein R may be 2-phenoxyphenyl, 2-bromothiophen-5-yl, or 2,5-dichlorophenyl; or an antibiotic potentiator having the formula: 
       
       
         
           
           
               
               
           
         
         wherein R may be fluoro, or chloro, or 
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
         or an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
       
       or
 an antibiotic potentiator having the formula: 
 
       
         
           
           
               
               
           
         
         wherein R 1  may be N-(4-(phenylamino)-N′-(phenyl)acetamide)amine, N-3-(N′,N′-dimethylamine)propylamine, N-(4-N′-phenylacetamide)amine, or hydroxyl, and R 2  may be tent-butyl, isopropyl, or phenyl, and R 3  may be phenyl, or 4-chlorophenyl, or an antibiotic potentiator having the structure: 
       
       
         
           
           
               
               
           
         
       
       or
 an antibiotic potentiator having the formula: 
 
       
         
           
           
               
               
           
         
         wherein R may be 1H-indazol-6-yl, or 3-(4-methoxyphenoxy)methyloxadiazol-5-yl-methyl, or 
         an antibiotic potentiator having the formula: 
       
       
         
           
           
               
               
           
         
         wherein wherein, R 1  and R 2  may each be separately hydrogen, methyl, chloro or methylthio, or a prodrug or comparable salt thereof. 
       
     
     
         2 . The method of  claim 1 , wherein the antibiotic is a beta-lactam antibiotic. 
     
     
         3 . The method of  claim 2 , wherein the antibiotic is a penicillinase-resistant beta-lactam antibiotic. 
     
     
         4 . The method of  claim 3 , wherein the penicillinase-resistant beta-lactam antibiotic is oxacillin. 
     
     
         5 . The method of any of  claims 1 - 4 , wherein the subject has been tested for a  staphylococcus  infection. 
     
     
         6 . The method of any of  claims 1 - 5 , wherein the subject is diagnosed with a  staphylococcus  infection. 
     
     
         7 . The method of any of  claims 1 - 5 , wherein the subject is at risk of acquiring a  staphylococcus  infection. 
     
     
         8 . The method of any of  claims 1 - 7 , wherein the subject has one or more symptoms of a  staphylococcal  infection. 
     
     
         9 . The method of  claim 1 , wherein the  staphylococcus  infection is  Staphylococcus aureus.    
     
     
         10 . The method of  claim 1 , wherein the  staphylococcus  infection is methicillin resistant  Staphylococcus aureus  (MRSA). 
     
     
         11 . The method of any of  claims 1 - 10 , wherein the subject has or is at risk for native valve endocarditis or prosthetic valve endocarditis. 
     
     
         12 . The method of  claim 11 , wherein the subject is administered about 2-3 g of oxacillin intravenously every 4 to 6 hours. 
     
     
         13 . The method of any of  claims 1 - 10 , wherein the subject has or is at risk for joint infection, meningitis, osteomyelitis, pneumonia, septicemia, sinusitis, or skin or soft tissue infection. 
     
     
         14 . The method of  claim 9 , wherein the subject is administered about 1-2 g of oxacillin intravenously or intramuscularly every 4 to 6 hours or about 500 mg to about 1 g of oxacillin orally every 4 to 6 hours. 
     
     
         15 . The method of any of  claims 1 - 10 , wherein treating a staphylococcal infection comprises reducing abscess formation or incidence or reducing bacterial load in the subject. 
     
     
         16 . The method of  claim 1 , further comprising administering a second antibiotic. 
     
     
         17 . The method of  claim 16 , wherein the second antibiotic is gentamicin or rifampin. 
     
     
         18 . The method of any of any of  claims 1 - 17 , further comprising administering a staphylococcal vaccine. 
     
     
         19 . The method of any of  claims 1 - 18 , wherein the antibiotic is administered at a dose of about 0.1 mg/kg to about 50 mg/kg. 
     
     
         20 . The method of  claim 19 , wherein the subject is a pediatric patient. 
     
     
         21 . The method of  claim 20 , wherein the pediatric patient is administered about 25 mg/kg to about 50 mg/kg of oxacillin intravenously or intramuscularly every 6 to 12 hours or about 12.5 mg/kg of oxacillin orally every 6 hours. 
     
     
         22 . The method of any of  claims 1 - 21 , wherein the antibiotic potentiator is administered at a dose of 0.1 mg/kg to about 100 mg/kg. 
     
     
         23 . The method of any of  claims 1 - 22 , whereby administration to a subject is oral, sublingual, sublabial, gastrointestinal, rectal, epicutaneous (topical), intradermal, subcutaneous, nasal, intravenous, intraarterial, intramuscular, intracardiac, intraosseous, intrathecal, intraperitoneal, intravesical, intravitreal, intracavernous, intravaginal, intrauterine, epidural, intracerebral and/or intracerebroventricular. 
     
     
         24 . The method of any of  claims 1 - 23 , wherein administration is topical, enteral, or parenteral. 
     
     
         25 . The method of any of  claims 1 - 32 , wherein administration is by application onto the skin, inhalation, an enema, eye drops, ear drops, absorption across mucosal membranes, the mouth, a gastric feeding tube, a duodenal feeding tube, a suppository, an injection into a vein, an injection into an artery, an injection into the bone marrow, an injection into muscle tissue, an injection into the brain, an injection into the cerebral ventricular system or an injection under the skin. 
     
     
         26 . The method of  claim 3 , wherein the penicillinase-resistant beta-lactam antibiotic is methicillin, nafcillin, cloxacillin, dicloxacillin or flucloxacillin. 
     
     
         27 . The method of any of  claims 1 - 26 , wherein the antibiotic and the antibiotic potentiator are administered in the same composition. 
     
     
         28 . The method of any of  claims 1 - 26 , wherein the antibiotic and the antibiotic potentiator are administered simultaneously. 
     
     
         29 . The method of any of  claims 1 - 26 , wherein the antibiotic is administered up to 24 hours prior to administration of the antibiotic potentiator. 
     
     
         30 . The method of any of  claims 1 - 26 , wherein the antibiotic potentiator is administered up to 24 hours prior to administration of the antibiotic. 
     
     
         31 . The method of any of  claims 1 - 26 , wherein the antibiotic and antibiotic potentiator are administered within 24 hours of each other. 
     
     
         32 . A pharmaceutical composition comprising an antibiotic and a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 1  may be -(4-chlorophenoxy)methyl, 1-(thiophen-2-yl)cyclopentyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 1-isopropyl-1H-pyrazol-5-yl, 2-(thiophen-2-yl)quinolin-4-yl, 2,3-dihyrdobenzo[b] [ 1,4]dioxin-6-yl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl, 2,6-difluorophenyl, 2-bromothiophen-5-yl, 2-chlorothiophen-5-yl, 2-naphthyl, 2-phenoxyphenyl, 2-phenylquinolin-4-yl, 2-tolyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, 3,4,5-trimethoxyphenyl, 3,5-dichlorophenyl, 3,5-dimethoxyphenyl, 3-bromophenyl, 3-chlorobenzo[b]thiophen-2-yl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-n-butoxyphenyl, 3-phenoxyphenyl, 3-tolyl, 3-trifluoromethylphenyl, 4-(2,6-dimethylmorpholinosulfonyl)phenyl, 4-(2-ethylpiperidin-1-ylsulfonyl)phenyl, 4-(2-methylpiperidin-1-ylsulfonyl)phenyl, 4-(2-phenylquinoline), 4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl, 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl, 4-(3,5-dimethylpiperidin-1-ylsulfonyl)phenyl, 4-(4,4-dimethyloxazolidin-3-ylsulfonyl)phenyl, 4-(morpholinosulfonyl)phenyl, 4-(N,N-diallyl sulfamoyl)phenyl, 4-(N,N-diethyl sulfamoyl)phenyl, 4-(N,N-diisobutylsulfamoyl)phenyl, 4-(N,N-dimethyl sulfamoyl)phenyl, 4-(N-ethyl-N-benzyl sulfamoyl)phenyl, 4-(N-ethyl-N-n-butyl-sulfamoyl)phenyl, 4-(N-ethyl-N-phenyl sulfamoyl)phenyl, 4-(N-isopropyl-N-benzylsulfamoyl)phenyl 4-(N-methyl-N-benzyl sulfamoyl)phenyl, 4-(N-methyl-N-cyclohexyl sulfamoyl)phenyl, 4-(N-methyl-N-n-butyl sulfamoyl)phenyl, 4-(N-methyl-N-phenyl sulfamoyl)phenyl, 4-(piperidin-1-ylsulfonyl)phenyl, 4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-benzoylphenyl, 4-benzylphenyl, 
         4-biphenyl, 4-chlorophenyl, 4-diphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-phenoxyphenyl, 4-tent-butylphenyl, 7-methoxybenzofuran-2-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-6-yl, benzofuran-2-yl, diphenylmethyl, methyl-4-benzoate, phenyl, or thiophen-2-yl, and 
         R 2  may be 1,2,3,4-tetrahydronaphthalen-6-yl, 2-(methylthio)phenyl, 2,3-dihydro-1,4-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-6-yl, 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl 2,5-dimethylphenyl, 2-bromothiophen-2-yl, 2-chlorophenyl, 2-chlorothiophen-2-yl, 2-chlorothiophen-5-yl, 2-furanyl, 2-methoxyphenyl, 2-pyridinyl, 3-(methylthio)phenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-methoxyphenyl, 3-pyridinyl, 4-chlorophenyl, 4-(methylthio)phenyl, 4-bromophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl, 4-pyridinyl, 4-trifluoromethoxyphenyl, 7-ethoxybenzofuran-2-yl, 7-methoxybenzofuran-2-yl, benzofuran-2-yl, benzyl, phenyl, or thiophen-2-yl, 
       
       
         
           
           
               
               
           
         
         wherein R may be 2-phenoxyphenyl, 2-bromothiophen-5-yl, or 2,5-dichlorophenyl; 
       
       
         
           
           
               
               
           
         
         wherein R may be fluoro, or chloro, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 1  may be N-(4-(phenylamino)-N′-(phenyl)acetamide)amine, N-3-(N′,N′-dimethylamine)propylamine, N-(4-N′-phenylacetamide)amine, or hydroxyl, and R 2  may be tent-butyl, isopropyl, or phenyl, and R 3  may be phenyl, or 4-chlorophenyl, 
       
       
         
           
           
               
               
           
         
         wherein R may be 1H-indazol-6-yl, or 3-(4-methoxyphenoxy)methyloxadiazol-5-yl-methyl, and 
       
       
         
           
           
               
               
           
         
         wherein wherein, R 1  and R 2  may each be separately hydrogen, methyl, chloro or methylthio, or a prodrug or comparable salt thereof. 
       
     
     
         33 . The pharmaceutical composition of  claim 32 , comprising a single unit dose of the selected antibiotic and selected compound. 
     
     
         34 . The pharmaceutical composition of  claim 32  or  33 , comprising at least an additional antibacterial agent. 
     
     
         35 . The pharmaceutical composition of  claim 34 , wherein the additional anti-bacterial agent is a further antibiotic, a staphylococcal vaccine composition or a polypeptide that specifically binds to a second Staphylococcal protein. 
     
     
         36 . The pharmaceutical composition of any of  claims 32 - 35 , wherein the composition is a pill, capsule, tablet, lozenge, troche, solution, cream, gel, paste, liquid or solid. 
     
     
         37 . A system for treating a bacterial infection comprising a pharmaceutically acceptable composition comprising an antibiotic and a pharmaceutically acceptable composition comprising an antibiotic potentiator selected from the group consisting of 
       
         
           
           
               
               
           
         
         wherein R 1  may be -(4-chlorophenoxy)methyl, 1-(thiophen-2-yl)cyclopentyl, 1,2,3,4-tetrahydronaphthalen-6-yl, 1-isopropyl-1H-pyrazol-5-yl, 2-(thiophen-2-yl)quinolin-4-yl, 2,3-dihyrdobenzo[b][1,4]dioxin-6-yl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl, 2,6-difluorophenyl, 2-bromothiophen-5-yl, 2-chlorothiophen-5-yl, 2-naphthyl, 2-phenoxyphenyl, 2-phenylquinolin-4-yl, 2-tolyl, 3-(2-chlorophenyl)-5-methylisoxazol-4-yl, 3,4,5-trimethoxyphenyl, 3,5-dichlorophenyl, 3,5-dimethoxyphenyl, 3-bromophenyl, 3-chlorobenzo[b]thiophen-2-yl, 3-chlorophenyl, 3-fluorophenyl, 3-methoxyphenyl, 3-n-butoxyphenyl, 3-phenoxyphenyl, 3-tolyl, 3-trifluoromethylphenyl, 4-(2,6-dimethylmorpholinosulfonyl)phenyl, 4-(2-ethylpiperidin-1-ylsulfonyl)phenyl, 4-(2-methylpiperidin-1-ylsulfonyl)phenyl, 4-(2-phenylquinoline), 4-(3,4-dihydroisoquinolin-2(1H)-ylsulfonyl)phenyl, 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)phenyl, 4-(3,5-dimethylpiperidin-1-ylsulfonyl)phenyl, 4-(4,4-dimethyloxazolidin-3-ylsulfonyl)phenyl, 4-(morpholinosulfonyl)phenyl, 4-(N,N-diallyl sulfamoyl)phenyl, 4-(N,N-diethyl sulfamoyl)phenyl, 4-(N,N-diisobutylsulfamoyl)phenyl, 4-(N,N-dimethyl sulfamoyl)phenyl, 4-(N-ethyl-N-benzyl sulfamoyl)phenyl, 4-(N-ethyl-N-n-butyl-sulfamoyl)phenyl, 4-(N-ethyl-N-phenyl sulfamoyl)phenyl, 4-(N-isopropyl-N-benzylsulfamoyl)phenyl 4-(N-methyl-N-benzyl sulfamoyl)phenyl, 4-(N-methyl-N-cyclohexyl sulfamoyl)phenyl, 4-(N-methyl-N-n-butyl sulfamoyl)phenyl, 4-(N-methyl-N-phenyl sulfamoyl)phenyl, 4-(piperidin-1-ylsulfonyl)phenyl, 4-(pyrrolidin-1-ylsulfonyl)phenyl, 4-benzoylphenyl, 4-benzylphenyl, 
         4-biphenyl, 4- chlorophenyl , 4-diphenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-phenoxyphenyl, 4-tert-butylphenyl, 7-methoxybenzofuran-2-yl, benzo[d]thiazol-2-yl, benzo[d]thiazol-4-yl, benzo[d]thiazol-6-yl, benzofuran-2-yl, diphenylmethyl, methyl-4-benzoate, phenyl, or thiophen-2-yl, and 
         R 2  may be 1,2,3,4-tetrahydronaphthalen-6-yl, 2-(methylthio)phenyl, 2,3-dihydro-1,4-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-2-yl, 2,3-dihydrobenzo[b][1,4]-dioxin-6-yl, 2,4-dichlorophenyl, 2,4-dimethoxyphenyl, 2,4-dimethylphenyl, 2,5-dichlorophenyl, 2,5-dichlorothiophen-3-yl 2,5-dimethylphenyl, 2-bromothiophen-2-yl, 2-chlorophenyl, 2-chlorothiophen-2-yl, 2-chlorothiophen-5-yl, 2-furanyl, 2-methoxyphenyl, 2-pyridinyl, 3-(methylthio)phenyl, 3,4,5-trimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4-dimethylphenyl, 3,5-dimethoxyphenyl, 3-methoxyphenyl, 3-pyridinyl, 4-chlorophenyl, 4-(methylthio)phenyl, 4-bromophenyl, 4-ethoxyphenyl, 4-fluorophenyl, 4-isopropylbenzyl, 4-methoxybenzyl, 4-methoxyphenyl, 4-pyridinyl, 4-trifluoromethoxyphenyl, 7-ethoxybenzofuran-2-yl, 7-methoxybenzofuran-2-yl, benzofuran-2-yl, benzyl, phenyl, or thiophen-2-yl, 
       
       
         
           
           
               
               
           
         
         wherein R may be 2-phenoxyphenyl, 2-bromothiophen-5-yl, or 2,5-dichlorophenyl; 
       
       
         
           
           
               
               
           
         
         wherein R may  be  fluoro, or chloro, 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         wherein R 1  may be N-(4-(phenylamino)-N′-(phenyl)acetamide)amine, N-3-(N′,N′-dimethylamine)propylamine, N-(4-N′-phenylacetamide)amine, or hydroxyl, and R 2  may be tent-butyl, isopropyl, or phenyl, and R 3  may be phenyl, or 4-chlorophenyl, 
       
       
         
           
           
               
               
           
         
         wherein R may  be  1H-indazol-6-yl, or 3-(4-methoxyphenoxy)methyloxadiazol-5-yl-methyl, and 
       
       
         
           
           
               
               
           
         
         wherein wherein, R 1  and R 2  may each be separately hydrogen, methyl, chloro or methylthio, or a prodrug or comparable salt thereof. 
       
     
     
         38 . The system of  claim 37 , wherein the antibiotic is in an aqueous formulation. 
     
     
         39 . The system of  claim 38 , wherein the antibiotic is in an aqueous formulation that is an intravenous solution or an aqueous formulation that is injectable into the patient or into an intravenous solution. 
     
     
         40 . The system of any of  claims 37 - 39 , wherein the antibiotic potentiator is in an aqueous formulation. 
     
     
         41 . The system of  claim 40 , wherein the antibiotic potentiator is in an aqueous formulation that is an intravenous solution or an aqueous formulation that is injectable into the patient or into an intravenous solution.