Patent EA-002808-B1 (EA)
Title: Betaines as adjuvants to susceptibility testing and antimicrobial therapy
Inventor: THORNTON CHARLES G
IPC: C12Q1/04
Filed: 1998-05-01
Abstract: 1. A method for testing a susceptibility of microorganism to a composition comprising an antibiotic, said method comprising exposing a microorganism, which has mycolic acid structures on the outer membrane thereof, to a composition comprising an antibiotic and a betaine-like detergent, and characterizing the susceptibility of said microorganism to said antibiotic based upon the viability of said microorganism in said composition. 2. The method of Claim 1, wherein said betaine-like detergent is selected from the group consisting of a CB-Like, SB-like, HSB-like, PB-like, CtB-like, PhB-like, SoB-like, RevB-like, AO-like, cAB-like, and ImB-like detergent. 3. The method of Claim 2, wherein said CB-like detergent has the structure   wherein R1 is C8-C22; α is -CH2-,-CH(OH)-, -(CO)-NH-CH2 CH2 CH2-, -O-, or -C(O)-; n is 0 or 1; β is -N<(+)>-, -P<(+)>-, or -S<(+)>-; R2 is -H, -CH3-, -C2H5-, -C3H7-, or -C4H9-; R3 is -H, -CH3-, -C2H5-, -C3H7-, or -C4H9-; R4 is -CH2-, -C2H4-, -C3H6-, -C4H8-, -C5H10-, -C6H12-, -CH2-C6H4-, -CmH2m-, -CH(OH)CH2 CH2-, -CH2 CH(OH) CH2-, or -CmH2m-1(OH)-, wherein m >=1; γ is -COO<(+)>. 4. The method of Claim 3, wherein said betain-like detergent is selected from the group consisting of N-(carboxymethyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS<(RTM)> No. 693-33-4), cococarboxymethylbetaine and CAS(RTM) No. 68424-94-2), N-(carboxymethyl)-N,N-dimethyl-9-octadecen-aminium, inner salt (CAS(RTM) No.871-37-4), N-(carboxymethyl)-N,N-dimethyl-3-((1-oxooctadecyl)amino)-1-propanaminium, inner salt (CAS(RTM) No.6179-44-8), 3-amino-N(carboxymethyl)-N,N-dimethyl-1-propanaminium N-C8-C22 acyl derivatives, inner salt (CAS(RTM) No.840-44-0), N-(carboxymethyl)-3-((12-hydroxy-1-oxo-9-octadecenyl)amino)-N,N-dimethyl-1-propanaminium, inner salt (CAS(RTM) No.71850-81-2), cocoamidopropyl carboxymethylbetaine (CAS(RTM)No.61789-39-7 and CAS(RTM) No.61789-40-0), N-(2-carboxyethyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No. 16527-85-8), N-(2-carboxyethyl)-N,N-dimethyl-1-tridecanaminium, inner salt (CAS(RTM) No. 132621-79-5), N-(2-carboxyethyl)-N,N-dimethyl-1-tetradecanaminium, inner salt (CAS(RTM) No.69725-38-3), N-(2-carboxyethyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS(RTM) No.42416-43-3), N-(2-carboxyethyl)-N,N-dimethyl-1-octadecanaminium, inner salt (CAS(RTM) No.30612-73-8), N-dodecyl-beta-alanine (CAS(RTM) No.1462-54-0), N-(3-carboxypropyl)-N,N-dimethyl-1-undecanaminium, inner salt (CAS(RTM) No.150147-53-8), N-(3-carboxypropyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No.15163-30-1), N-(3-carboxypropyl)-N,N-dimethyl-1-tetradecanaminium, inner salt (CAS(RTM) No.146959-90-2), N-(3-carboxypropyl)-N,N-dimethyl-1-pentadecanaminium, inner salt (CAS(RTM) No.146959-91-3), N-(3-carboxypropyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS(RTM) No.71695-32-4), N-(3-carboxypropyl)-N,N-dimethyl-1-octadecanaminium, inner salt (CAS(RTM) No.78195-27-4), N-(4-carboxybutyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No.120139-51-7), N-(5-carboxypentyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No.76392-97-7), N-(5-carboxypentyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS(RTM) No.73565-98-7), N-(6-carboxyhexyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No.132621-80-8), 4-carboxy-N-dodecyl-N,N-dimethyl-benzenemethanaminium, inner salt (CAS(RTM) No.71695-31-3), 2-carboxy-N-dodecyl-N,N-dimethyl-benzenemethanaminium, inner salt (CAS(RTM) No.71695-34-6), 4-carboxy-N-hexadecyl-N,N-dimethyl-benzenemethanaminium, inner salt (CAS(RTM) No.71695-33-5), 2-carboxy-N-hexadecyl-N,N-dimethyl-benzenemethanaminium, inner salt (CAS(RTM) No.71695-35-7), tallow glycinate (CAS(RTM) No.707-46-8), soyamidopropyl carboxymethylbetaine, and babassuamidopropyl carboxymethylbetaine. 5. The method of Claim 4, wherein said carboxybetaine is N-(3-carboxypropyl)-N,N-dimethyl-1-octadecanaminium, inner salt (CB-18) (CAS(RTM) No.78195-27-4). 6. The method of Claim 2, wherein said SB-like detergent is selected from the group consisting of SB-18, SB-16, SB-14 and SB-12. 7. The method of any one of Claims 1-6, wherein said composition comprises two or more betaine-like detergents. 8. The method of Claim 1, wherein said antibiotic is a member of a class selected from the group consisting of a β-lactam antibiotic, an aminoglycoside, an aminocyclitol, a quinolone, a tetracycline, a macrolide, a lincosamide, a glycopeptide, a lipopeptide, a polypeptide antibiotic, a sulfonamide, trimethoprim, chloramphenicol, isoniazid, a nitroimidazole, a rifampin, a nitrofuran, methenamine, and mupirocin. 9. The method of Claim 8, wherein said β-lactam antibiotic is selected from the group consisting of penicillin, cephalosporin, monobactam and carbapenem antibiotics. 10. The method of Claim 9, wherein said penicillin is selected from the group consisting of azlocillin, methicillin, nafcillin, cloxacillin, dicloxacillin, oxacillin, ampicillin, bacampicillin, carbenicillin, ticarcillin, mezlocillin and piperacillin. 11. The method of Claim 9, wherein said cephalosporin is selected from the group consisting of cefoxitin, cefoperazone, ceftazidime, ceftriaxone, cefadroxil, cefazolin, cephalexin, cephaloridine, cephalothin, cephapirin, cephradine, cefaclor, cefamandole, cefonicid, ceforanide, cefprozil, cefuroxime, loracarbef, cefmetazole, cefotetan, cefixime, cefotaxime, cefpodoxime, and ceftizoxime. 12. The method of Claim 9, wherein said monobactam is aztreonam. 13. The method of Claim 9, wherein said carbapenem is selected from the group consisting of imipenem, meropenem, panipenem, and biapenem. 14. The method of any one of Claims 8-13, wherein said composition further comprises β-lactamase inhibitor. 15. The method of Claim 14 wherein said β-lactamase inhibitor is selected from the group consisting of clavulanic acid, sulbactam, and tazobactam. 16. The method of Claim 8, wherein said antibiotic is said aminoglycoside or said aminocyclitol. 17. The method of Claim 16, wherein said aminoglycoside or aminocyclitol is selected from the group consisting of streptomycin, kanamycin, gentamicin, tobramycin, amikacin, sisomicin, netilmicin, neomycin, framycetin and paromomycin. 18. The method of Claim 8, wherein said quinolone is selected from the group consisting of naladixic acid, oxolinic acid, cinoxacin, flumequine, miloxacin, rosoxacin, pipemidic acid, norfloxacin, enoxacin, ciprofloxacin, ofloxacin, lomefloxacin, temafloxacin, fleroxacin, pefloxacin, amifloxacin, sparfloxacin, levofloxacin, clinafloxacin. 19. The method of Claim 8, wherein said macrolide is selected from the group consisting of erthromycin, oleandomycin, spiramycin, josamycin, rosaramicin, clarithromycin, azithromycin, dirithromycin, roxithromycin, flurithromycin, and rokitamycin. 20. The method of Claim 8, wherein said composition two or more antibiotics. 21. The method of Claim 20, wherein said antibiotics are a sulfonamide and trimethoprim. 22. The method of Claim 21, wherein said sulfonamide is sulfamethoxazole. 23. The method of Claim 8 wherein said rifampicin is selected from the group consisting of rifampin, rifamycin SV, rifamycin B (rifamide) and rifabutin. 24. The method of Claim 1 wherein said antibiotic is selected the group consisting of amikacin, azithromycin, any β-lactam in combination with any of the β-lactamase inhibitors, capreomycin, cefmetazole, cefoxitin, ciprofloxacin, clarithromycin, clofazamine, cycloserine, dapsone, erythromycin, ethambutol, ethionamide, imipenem, isoniazid, kanamycin, minocycline, ofloxacin, paraamino salicylic acid, prothionamide, pyrazinamide, rifampin, rifabutin, sparfloxacin, sulfamethoxazole with trimethoprim, streptomycin, tetracycline, thiacetazole and viomycm. 25. A method of antimicrobial therapy for a patient infected with, or at risk of being infected with, a microorganism, which has mycolic acid structures on the outer membrane thereof, said method comprising co-administering a betaine-like detergent and an antibiotic to said patient in an amount and for a length of time sufficient to kill said microorganism. 26. The method of Claim 55, wherein said betaine-like detergent is selected from the group consisting of a CB-like, SB-like, HSB-like, PB-like, CtB-like, PhB-like, SoB-like, RevB-like, AO-like, cAB-like, and ImB-like detergent. 27. The method of Claim 26, wherein said CB-like detergent has the structure   wherein R1 is C8-C22; α is -CH2-,-CH(OH)-, -(CO)-NH-CH2 CH2 CH2-, -O-, or -C(O)-; n is 0 or 1; β is -N<(+)>-, -p<(+)>- or -S<(+)>-; R2 is -H, -CH3-, -C2H5-, -C3H7-, or -C4H9-; R3 is -H, -CH3-, -C2H5-, -C3H7-, or -C4H9-; R4 is -CH2-, -C2H4-, -C3H6-, -C4H8-, -C5H10-, -C6H12-, -CH2-C6H4-, -CmH2m-, -CH(OH) CH2 CH2-, -CH2 CH(OH) CH2-, or -CmH2m-1 (OH)-, wherein m>=1; γ is -COO<(+)>. 28. The method of Claim 27, wherein said CB-like detergent is selected from the group consisting of N-(carboxymethyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS(RTM) No. 693-33-4), cococarboxymethylbetaine and CAS(RTM) No. 68424-94-2), N-(carboxymethyl)-N,N-dimethyl-9-octadecen-1-aminium, inner salt (CAS(RTM) No.871-37-4), N-(carboxymethyl)-N,N-dimethyl-3-((1-oxooctadecyl)amino)-1-propanaminium, inner salt (CAS(RTM) No.6179-44-8), 3-amino-N(carboxymethyl)-N,N-dimethyl-1-propanaminium N-C8-C22 acyl derivatives, inner salt (CAS(RTM) No.840-44-0), N-(carboxymethyl)-3-((12-hydroxy-1-oxo-9-octadecenyl)amino)-N,N-dimethyl-1-propanaminium, inner salt (CAS(RTM) No. 71850-81-2), cocoamidopropyl carboxymethylbetaine (CAS(RTM) No.61789-39-7 and CAS(RTM) No.61789-40-0), N-(2-carboxyethyl)-N,N-dimethyl-1-dodecanaminium, inner salt (CAS(RTM) No. 16527-85-8), N-(2-carboxyethyl)-N,N-dimethyl-1-tridecanaminium, inner salt (CAS(RTM) No. 132621-79-5), N-(2-carboxyethyl)-N,N-dimethyl-1-tetradecanaminium, inner salt (CAS(RTM) No. 69725-38-3), N-(2-carboxyethyl)-N,N-dimethyl-1-hexadecanaminium, inner salt (CAS(RTM) No. 42416-4