Bis-amino acid based compound and use thereof
Compositions comprising bis(tryptophan) derivatives are provided that act as antimicrobials. Also provided are methods for reversing antibiotic resistance in a bacterium, or recovering or enhancing antimicrobial activity of an antibiotic against a variety of microbes, by co-administration with a bis(tryptophan) derivative.
1. An antimicrobial composition comprising a bis(tryptophan) derivative, wherein said bis(tryptophan) derivative comprises: (i) an arenyl, an alkyl, an aralkyl, or an unsaturated spacer; (ii) a charged ammonium moiety; and (iii) an indole in a tryptophan residue.
2. The antimicrobial composition of claim 1 , wherein said bis(tryptophan) derivative is selected from the group consisting of (2S,2′S)-1,1′-(1,3-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2R,2′R)-1,1′-(1,3-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2S,2′S)-1,1′-(1,2-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2S,2′S)-1,1′-(1,4-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, and (S)-1-((12-((R)-2-ammonio-3-(1H-indol-3-yl)propanamido)dodecyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-aminium chloride.
3. A method of recovering or enhancing antimicrobial activity of an antibiotic wherein said method comprising administering to a microbe the antibiotic with the antimicrobial composition comprising a bis(tryptophan) derivative of claim 1 , and wherein said microbe is a bacterium.
4. The method of claim 3 , wherein said bis(tryptophan) derivative is selected from the group consisting of (2S,2′S)-1,1′-(1,3-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2R,2′R)-1,1′-(1,3-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2S,2′S)-1,1′-(1,2-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, (2S,2′S)-1,1′-(1,4-phenylenebis(azanediyl))bis(3-(1H-indol-3-yl)-1-oxopropan-2-aminium) chloride, and (S)-1-((12-((R)-2-ammonio-3-(1H-indol-3-yl)propanamido)dodecyl)amino)-3-(1H-indol-3-yl)-1-oxopropan-2-aminium chloride.
5. The method of claim 3 , wherein said bacterium is an efflux pump expressing Gram-positive or Gram-negative bacterium, and said antibiotic resistance is efflux pump-mediated resistance.
6. The method of claim 5 , wherein said bacterium is an Escherichia coli strain or a Staphylococcus aureus strain.
7. The method of claim 3 , wherein said antibiotic is administered at a concentration below its minimum inhibitory concentration.
8. The method of claim 3 , wherein said bis(tryptophan) derivative is administered at a concentration below its minimum inhibitory concentration.
9. The method of claim 3 , wherein said antibiotic and said bis(tryptophan) derivative are both administered at a concentration below their minimum inhibitory concentrations.
10. The method of claim 3 , wherein said antibiotic is selected from the group consisting of ampicillin, kanamycin, tobramycin, erythromycin, rifampicin, norfloxacin, and tetracycline.
11. The method of claim 10 , wherein said antibiotic is ampicillin, norfloxacin or tetracycline.