Chitosan derivatives, compositions and related methods of use
Described herein are methods and compositions using chitosan derivatives to treat and/or inhibit acquisition of multiple drug resistance (MDR). Also described herein are methods and compositions using chitosan derivatives in combination with an antibacterial agent to treat a bacterial infection and/or inhibit growth of bacteria, for example, resulting in a synergistic or sensitizing effect.
1. A method of inhibiting the growth of a bacterium or killing a bacterium in a subject, comprising contacting the bacterium with a derivatized chitosan and an anti-bacterial agent in an effective combined amount, thereby inhibiting the growth of the bacterium or killing a bacterium, wherein the anti-bacterial agent and the derivatized chitosan are present at a concentrations, or administered at doses, which result in a fractional inhibitory concentration (FIC) of less than or equal to 0.5,
wherein the derivatized chitosan comprises a chitosan of the following formula (I):
wherein:
n is an integer between 20 and 6000; and
each R 1 is independently selected for each occurrence from hydrogen, acetyl,
wherein at least 25% of R 1 substituents are H, at least 1% of R 1 substituents are acetyl, and at least 2% of R 1 substituents are
2. The method of claim 1 , wherein the inhibition is at least 2 times greater than the sum of the inhibition seen with either the anti-bacterial agent or the derivatized chitosan used alone.
3. The method of claim 1 , wherein the bacterium is resistant to the derivatized chitosan when the derivatized chitosan is administered without the anti-bacterial agent.
4. The method of claim 1 , wherein the anti-bacterial agent is present at a concentration, or administered at a dose, which would not result in inhibition of bacterial growth or killing the bacterium in the absence of the derivatized chitosan.
5. The method of claim 1 , wherein the derivatized chitosan is present at a concentration, or administered at a dose, which would not result in inhibition of bacterial growth or killing the bacterium in the absence of the anti-bacterial agent.
6. The method of claim 1 , wherein the anti-bacterial agent and derivatized chitosan are present at a concentration, or administered at a dose, which result in a bactericidal activity at least 2 logs more effective than the most effective activity in the absence of the chitosan derivative or anti-bacterial agent.
7. The method of claim 1 , wherein the anti-bacterial agent is selected from aminoglycosides; beta-lactam antibiotics; macrolides; antibiotic polypeptides; antibiotic lipopeptides; antibiotic glycopeptides; monobactams; quinolones; sulfonamides; and tetracyclines, and the bacterium is selected from Gram-positive and Gram-negative bacterium.
8. The method of claim 1 , wherein the anti-bacterial agent is selected from Ciprofloxacin, Rifampicin, Neomycin, silver and Gentamicin, and the bacterium is Pseudomonas aeruginosa.
9. The method of claim 1 , wherein the anti-bacterial agent is present at less than 8 μg/ml.
10. The method of claim 1 , wherein the derivatized chitosan is present at less than 16 μg/ml.
11. The method of claim 10 , wherein the derivatized chitosan is present at less than 8 μg/ml.
12. The method of claim 1 , wherein the molecular weight of the derivatized chitosan is from 25 to 100 kDa.
13. The method of claim 12 , wherein the molecular weight of the derivatized chitosan is from 20 to 30 kDa.
14. The method of claim 1 , wherein the polydispersity index of the derivatized chitosan is from 1.0 to 2.5.
15. The method of claim 1 , wherein the derivatized chitosan is functionalized at between 5% and 50%.