Chitosan-derivative compounds and methods of controlling microbial populations

• US 20070281904A1
• Filed: 01/24/2007
• Published: 12/06/2007
• Est. Priority Date: 06/02/2006
• Status: Active Grant

• Current Assignee: Hawaii Chitopure Incorporated, Synedgen, Inc.
• Original Assignee: Synedgen, Inc.
• Inventors: Baker, Shenda, Wiesmann, William P., Ryan, Shannon
• Granted Patent: US 8,119,780 B2
• Time in Patent Office: Days
• US Class Current: 514/55
• CPC Class Codes: A61K 31/722 Chitin, chitosan
• CPC Class Codes: A61K 8/736 Chitin; Chitosan; Derivatives thereof
• CPC Class Codes: A61L 2/232 layered or coated
• CPC Class Codes: A61L 2/235 cellular, porous or foamed
• CPC Class Codes: A61L 2202/23 Containers, e.g. vials, bottles, syringes, mail
• CPC Class Codes: A61L 2202/24 Medical instruments, e.g. endoscopes, catheters, sharps
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61Q 11/00 Preparations for care of the teeth, of the oral cavity or of dentures; Dentifrices, e.g. toothpastes; Mouth rinses
• CPC Class Codes: A61Q 17/005 Antimicrobial preparations
• CPC Class Codes: C08B 37/003 Chitin, i.e. 2-acetamido-2-deoxy-(beta-1,4)-D-glucan or N-acetyl-beta-1,4-D-glucosamine; Chitosan, i.e. deacetylated product of chitin or (beta-1,4)-D-glucosamine; Derivatives thereof
• CPC Class Codes: C08L 5/08 Chitin; Chondroitin sulfate; Hyaluronic acid; Derivatives thereof
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention is directed to chitosan-derivative compounds and structures, methods of making chitosan-derivative compounds and methods for controlling, inhibiting and enhancing microbial populations in a variety of environments. The present invention is also directed to the control, inhibition and enhancement of microbial populations in animals, particularly humans. The microbial populations include bacteria, viruses and other pathogens where control of microbial populations are a necessity. The chitosan-derivative compounds of the present invention include chitosan-arginine compounds, related chitosan-L/D unnatural amino acid compounds, chitosan-acid amine compounds, chitosan-L/D natural amino acid derivative compounds, co-derivatives of the chitosan-derivative compounds, salts of the chitosan derivative compounds, and chitosan-guanidine compounds.

Claims

1. A compound comprising functionalized chitosan-derivatives, wherein said functionalization is between 2% and 50%, said chitosan-derivatives having a molecular weight in the range of 25,000 to 1,000,000 Da, having a pH between 1 and 10, having ultra-low endotoxin levels, and in effective amounts for controlling microbial populations, formulated so as to balance said functionalization with toxicity.

2. A compound as recited in claim 1, wherein said pH is between 6.8 and 7.4.

3. A compound as recited in claim 2, wherein said molecular weight is between 25,000 and 350,000 Da.

4. A compound as recited in claim 3, wherein said functionalization is between 6% and 30%.

5. A compound as recited in claim 4, wherein said chitosan-derivative compounds is chitosan-arginine.

6. A compound as recited in claim 5, wherein said microbial populations comprise bacteria, mycobacteria, mycoplasma, viruses, protozoas and prions.

7. A compound as recited in claim 6, wherein said bacteria comprise Gram-negative bacteria selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas fluorescens, Acinetobacter baumannii, Klebsiella pneumoniae, Shigella flexneri, Salmonella typhi, and Proteus mirabilis.

8. A compound as recited in claim 6, wherein said bacteria comprise Gram-positive bacteria selected from the group consisting of Bacillus subtilis, Staphlococcus aureus, Staphlococcus epidermidis, Streptococcus mutans and Streptococcus pyogenes.

9. A compound as recited in claim 6, wherein said viruses are selected from the group consisting of vaccinia virus (Copenhagen strain), herpes simplex 1 (sp7 strain) and encephalomyocarditis virus.

10. A compound as recited in claim 6, wherein said viruses is influenza A (H1, N1).

11. A compound as recited in claim 6, wherein said functionalization is 7%.

12. A compound as recited in claim 6, wherein said functionalization is 30%.

13. A compound as recited in claim 4, wherein said chitosan-derivative compounds comprise chitosan-lysine.

14. A compound as recited in claim 4, wherein said chitosan-derivative compounds comprise related chitosan-unnatural amino acid compounds and racemic mixtures thereof.

15. A compound as recited in claim 14, wherein said unnatural amino acid compounds are selected from the group consisting of 2,3-diaminopropionic acid;

2,4-diaminobutyric acid;

2,5-diaminopentanoic acid (ornithine) and their guanidinylated derivatives.

16. A compound as recited in claim 4, wherein said chitosan-derivative comprise chitosan-acid amine compounds.

17. A compound as recited in claim 16, wherein said chitosan-acid amine compounds are selected from a group consisting of 2-amino-ethanoic acid, 3-amino-propanoic acid, 4-amino-butanoic acid, 5-amino-pentanoic acid, 6-amino-hexanoic acid and their guanidinylated derivatives.

18. A compound as recited in claim 4, wherein said chitosan-derivative compounds comprise chitosan-natural amino acid compounds and racemic mixtures thereof.

19. A compound as recited in claim 18, wherein said related chitosan natural amino acids are selected from a group consisting of histidine (H), aspartic acid (D), and glutamic acid (E).

20. A compound as recited in claim 4, and further comprising co-derivatives of said compounds.

21. A compound as recited in claim 20, wherein said co-derivatives are selected from the group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, cellular growth factors, iron chelating agents, antioxidants, indicating fluorescent markers, cell growth factors, lysine (K), arginine (R), histidine (H), aspartic acid (D), glutamic acid (E);

serine (S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), cysteine (C);

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

22. A compound as recited in claim 4, and further comprising salts of said compounds.

23. A compound as recited in claim 22, wherein said salts of said compounds are selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

24. A compound as recited in claim 4, wherein said compounds are formed into soluble powers, films, coatings, gels, laminates, nanoparticles, woven fibers, non-woven fibers, and encapsulated compounds.

25. A compound as recited in claim 2, wherein the chitosan-derivative compound is chitosan-guanidine.

26. A compound as recited in claim 25, wherein said microbial populations comprise bacteria, mycobacteria, mycoplasma, viruses, protozoas and prions.

27. A compound as recited in claim 26, wherein said bacteria comprise Gram-negative bacteria selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas fluorescens, Acinetobacter baumannii, Klebsiella pneumoniae, Shigella flexneri, Salmonella typhi, and Proteus mirabilis.

28. A compound as recited in claim 25, wherein said bacteria comprise Gram-positive bacteria selected from the group consisting of Bacillus subtilis, Staphlococcus aureus, Staphlococcus epidermidis, Streptococcus mutans and Streptococcus pyogenes.

29. A compound as recited in claim 25 and further comprising salts of said chitosan-guanidine compound.

30. A compound as recited in claim 29, wherein said salts are selected from a group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate and glutamate.

31. A compound as recited in claim 2 wherein said chitosan-derivative compound is a chitosan-guanidine derivative.

32. A compound as recited in claim 31 wherein said derivative selected from the group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, cellular growth factors, iron chelating agents, antioxidants, indicating fluorescent markers, cell growth factors, lysine (K), arginine (R), histidine (H), aspartic acid (D), glutamic acid (E);

serine (S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), cysteine (C);

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

33. A compound as recited in claim 31 and further comprising salts of said chitosan-guanidine derivative compounds.

34. A compound as recited in claim 33, wherein said salts are selected from a group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate and glutamate.

35. A method for controlling microbial activity in an individual comprising administering functionalized chitosan-derivative compounds that are soluble at physiologic pH, in a therapeutically effective amount and in a therapeutically effective excipient.

36. A method as recited in claim 35, and further comprising functionalizing said compound between 2% and 50%.

37. A method as recited in claim 36, wherein said pH is between 6.8 and 7.4.

38. A method as recited in claim 37, wherein said compound is chitosan-arginine, and further comprising functionalizing said chitosan-arginine to at least 6% but no more than 30%.

39. A method as recited in claim 38, wherein said treatment comprises promoting wound healing.

40. A method as recited in claim 39, further comprising treating second and third degree burn wounds.

41. A method as recited in claim 39, further comprising treating chronic ulcers.

42. A method as recited in claim 38, wherein said treatment comprises preventing biofilm formation.

43. A method as recited in claim 38, wherein said treatment comprises inhibiting planktonic growth of Gram-negative bacteria.

44. A method as recited in claim 43, wherein said planktonic growth comprises cell culture media.

45. A method as recited in claim 44 wherein said Gram-negative bacteria are selected from the group consisting of Escherichia coli, Pseudomonas aeruginosa, Pseudomonas fluorescens, Acinetobacter baumannii, Klebsiella pneumoniae, Shigella Flexneri, Salmonella typhi and Proteus mirabilis.

46. A method as recited in claim 38, wherein said treatment comprises inhibiting planktonic growth of Gram-positive bacteria.

47. A method as recited in claim 46, wherein said planktonic growth comprises cell culture media.

48. A method as recited in claim 47, wherein said Gram-positive bacteria are selected from the group consisting of Bacillus subtilis, Staphlococcus aureus, Staphylococcus epidermidis, Streptococcus mutans and Streptococcus pyogens.

49. A method as recited in claim 38, wherein said treatment further comprising preventing viral infections.

50. A method as recited in claim 38, and further comprising utilizing said compound to bind viruses to surfaces.

51. A method as recited in claim 49 or 50, wherein said viruses are selected from the group consisting of influenza A (H1, N1).

52. A method as recited in claim 49 or 50, wherein said viruses are selected from the group consisting of vaccinia virus (Copenhagen strain), herpes simplex I (sp7 strain), and encephalomyocarditis virus.

53. A method as recited in claim 39, further comprising controlling microbial populations in animals.

54. A method as recited in claim 39, further comprising controlling microbial populations in humans.

55. A method as recited in claim 37, wherein said compound is chitosan-guanidine.

56. A method as recited in claim 37, wherein said compound is chitosan-lysine.

57. A method as recited in claim 37, said chitosan-derivative compounds comprise related chitosan-unnatural amino acid compounds and racemic mixtures thereof.

58. A method as recited in claim 57, wherein said unnatural amino acid compounds are selected from the group consisting of 2,3-diaminopropionic acid;

2,4-diaminobutyric acid;

2,5-diaminopentanoic acid (ornithine) and their guanidinylated derivatives.

59. A method as recited in claim 37, wherein said chitosan-derivative comprise chitosan-acid amine compounds.

60. A method as recited in claim 59, wherein said chitosan-acid amine compounds are selected from a group consisting of 2-amino-ethanoic acid, 3-amino-propanoic acid, 4-amino-butanoic acid, 5-amino-pentanoic acid, 6-amino-hexanoic acid and their guanidinylated derivatives.

61. A method as recited in claim 37, wherein said chitosan-derivative compounds comprise chitosan-natural amino acid compounds and racemic mixtures thereof.

62. A method as recited in claim 61, wherein said related chitosan natural amino acids are selected from a group consisting of histidine (H), aspartic acid (D), and glutamic acid (E).

63. A method as recited in claim 37, and further comprising co-derivatives of said compounds.

64. A method as recited in claim 63, wherein said co-derivatives are selected from the group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, cellular growth factors, iron chelating agents, antioxidants, indicating fluorescent markers, cell growth factors, lysine (K), arginine (R), histidine (H), aspartic acid (D), glutamic acid (E);

serine (S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), cysteine (C);

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

65. A method as recited in claim 37, and further comprising salts of said compounds.

66. A method as recited in claim 65, wherein said salts of said compounds are selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

67. A method as recited in claim 37, and further comprising forming said compounds into soluble powers, films, coatings, gels, laminates, nanoparticles, woven fibers, non-woven fibers, and encapsulated compounds.

68. A method as recited in claim 37, wherein said chitosan-derivatives are chitosan-guanidine derivatives.

69. A method as recited in claim 68, wherein said derivatives are selected from the group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, cellular growth factors, iron chelating agents, antioxidants, indicating fluorescent markers, cell growth factors, lysine (K), arginine (R), histidine (H), aspartic acid (D), glutamic acid (E);

serine (S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), cysteine (C);

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

70. A method as recited in claim 68, and further comprising salts of said chitosan-guanidine derivatives.

71. A method as recited in claim 70, wherein said salts are selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate and glutamate.

72. A method as recited in claim 55 and further comprising salts of said chitosan-guanidine.

73. A method as recited in claim 72, wherein said salts are selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate and glutamate.

74. A process for making chitosan-derivative compounds comprising:

(a) preactivating acid derivative including boc protection

(b) increasing pH of said chitosan;

(c) uniformly adding said preactivated derivative to said chitosan in ratios relative to amines on said chitosan;

(d) initiating a coupling reaction between said chitosan and said derivative;

(e) reacting free acid derivative with amine on said chitosan;

(f) forming a viscous chitosan-derivative solution;

(g) controlling pH and salts of said solution by dialysis;

(h) forming said chitosan-derivative compound;

(i) dialyzing said chitosan-derivative compound with desired salts; and

(j) drying said compound and producing said chitosan-derivative compound.

75. A process as recited in claim 74, and further comprising:

(a) deprotecting said compound and removing existing boc; and

(b) controlling time for said deprotection step and forming desired molecular weight of said chitosan-derivative compound.

76. The process as recited in claim 75 comprising utilizing an activation group, wherein said activation group is selected from the group consisting of EDC, NHS, HBTU and HoBt.

77. The process as recited in claim 76, comprising utilizing a protection group, wherein said protection group is FMOC.

78. The process as recited in claim 77, and further comprising activating boc-derivative in-situ.

79. The process as recited in claim 78, and further comprising utilizing counterions in said dialysis.

80. The process as recited in claim 79 and further comprising deprotecting lyophilized intermediate utilizing 95% trifluoroacetic acid in sufficient quantities to dissolve said intermediate.

81. A chitosan-derivative compounds for controlling microbial populations comprising:

82. A compound as recited in claim 81, and further comprising an increased charge density, a molecular weight between 25,000 and 350,000 Da, solubility at pH between 6.8 and 7.4, wherein said q is at least 0.20 and said functionalization is between 6% and 30%.

83. A compound as recited in claim 82 wherein X is selected from the group consisting of:

84. A compound for controlling microbial populations comprising:

85. A compound as recited in claim 84, and further comprising an increased charge density, a molecular weight between 25,000 and 350,000 Da, solubility at pH between 6.8 and 7.4, wherein said q is at least 0.20 and said functionalization is between 6% and 30%.

86. A chitosan-derivative compound for controlling microbial populations comprising:

87. A compound as recited in claim 86, wherein X′

is selected from the group consisting of;

88. A compound as recited in claim 86, wherein X′

is selected from the group consisting of;

89. A chitosan-derivative compound for controlling microbial populations comprising:

90. A compound as recited in claim 89 wherein X″

is selected from the group consisting of;

91. A chitosan-derivative compound for controlling microbial population comprising:

92. A compound as recited in claim 91, wherein X′

″

is selected from the group of charged natural amino acids consisting of lysine (pka ˜

10), histidine (pka ˜

6).

93. A compound as recited in claim 91, wherein X′

″

is selected from the group consisting of;

94. A compound for controlling microbial populations comprising:

95. A chitosan-derivative compound for controlling microbial populations comprising:

96. A compound as recited in claim 95, wherein X is selected from the group consisting of:

97. A compound as recited in claim 95, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

98. A compound as recited in claim 95, wherein Y is selected from the group consisting of Y lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

99. A compound as recited in claim 95, wherein Y is selected from the group consisting of tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

100. A chitosan-derivative compound for controlling microbial populations comprising:

101. A compound as recited in claim 100 wherein X′

is selected from the group consisting of

102. A compound as recited in claim 100, wherein X′

is selected from the group consisting of;

103. A compound as recited in claim 100, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

104. A compound as recited in claim 100, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

105. A compound as recited in claim 100, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

106. A chitosan-derivative compound for controlling microbial populations comprising:

107. A compound as recited in claim 106, wherein X″

is selected from the group consisting of;

108. A compound as recited in claim 106, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

109. A compound as recited in claim 106, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

110. A compound as recited in claim 106, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

111. A chitosan-derivative compound for controlling microbial populations comprising:

112. A compound as recited in claim 111, wherein X′

″

is selected from the group of charged natural amino acids consisting of lysine (pka ˜

10), histidine (pka ˜

6), aspartic acid (asp) and glutamic acid (glu), where X′

″

≠

Y.

113. A compound as recited in claim 111, wherein X′

″

is selected from the group consisting of;

114. A compound as recited in claim 111, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

115. A compound as recited in claim 111, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys), where X′

″

≠

Y.

116. A compound as recited in claim 111, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile), where X′

″

≠

Y.

117. A chitosan-derivative compound for controlling microbial populations comprising:

118. A compound as recited in claim 117, wherein Z is selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

119. A compound as recited in claim 117, wherein X is selected from the group consisting of:

120. A chitosan-derivative compound for controlling microbial populations comprising:

121. A compound as recited in claim 120, wherein Z selected from a group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

122. A compound as recited in claim 120, wherein X′

is selected from the group consisting of;

123. A compound as recited in claim 120, wherein X′

is selected from the group consisting of;

124. A chitosan-derivative compound for controlling microbial populations comprising:

125. A compound as recited in claim 124, wherein Z is selected from a group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

126. A compound as recited in claim 124, wherein X″

is selected from the group consisting of;

127. A chitosan-derivative compound for controlling microbial populations comprising:

128. A compound as recited in claim 127, wherein Z is selected from the group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, and glutamate.

129. A compound as recited in claim 127, wherein X′

″

is selected from the group consisting of;

is selected from the group of charged natural amino acids consisting of lysine (pka ˜

10), histidine (pka ˜

6), aspartic acid (asp) and glutamic acid (glu).

130. A compound as recited in claim 127, wherein X′

″

is selected from the group of polar side chain containing L/D amino acids consisting of;

serine(S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), and cysteine (C).

131. A compound as recited in claim 127, wherein X′

″

is selected from the group of nonpolar side chain containing L/D amino acids consisting of;

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

132. A compound as recited in claim 127, wherein X′

″

is selected from the group consisting of;

133. A chitosan derivative compound for controlling microbial population comprising:

134. A compound as recited in claim 133, wherein Z is selected from the group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

135. A compound as recited in claim 133, wherein X is selected from the group consisting of:

136. A compound as recited in claim 133, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

137. A compound as recited in claim 133, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), praline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

138. A compound as recited in claim 133, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

155. A compound as recited in claim 138, wherein X′

″

is selected from the group of polar side chain containing L/D amino acids consisting of;

serine(S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), and cysteine (C), where X′

″

≠

Y.

139. A chitosan-derivative compound for controlling microbial population comprising:

140. A compound as recited in claim 139, wherein Z is selected from a group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

141. A compound as recited in claim 139, wherein X′

is selected from the group consisting of;

142. A compound as recited in claim 139, wherein X′

is selected from the group consisting of;

144. A compound as recited in claim 139, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), praline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

145. A compound as recited in claim 139, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

143. A compound as recited in 139, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

146. A chitosan-derivative compound for controlling microbial populations comprising:

147. A compound as recited in claim 146, wherein Z is selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

148. A compound as recited in claim 146, wherein X″

is selected from the group consisting of;

149. A compound as recited in claim 146 wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

150. A compound as recited in claim 146, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gin), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

151. A compound as recited in claim 146, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

152. A chitosan-derivative compound for controlling microbial populations comprising:

153. A compound as recited in claim 152, wherein Z is selected from the group consisting of:

chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

154. A compound as recited in claim 152, wherein X′

″

is selected from the group of charged natural amino acids consisting of lysine (pka ˜

10), histidine (pka ˜

6), aspartic acid (asp) and glutamic acid (glu), where X′

″

≠

Y.

156. A compound as recited in claim 152, wherein X′

″

is selected from the group of nonpolar side chain containing L/D amino acids consisting of;

glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W), where X′

″

≠

Y.

157. A compound as recited in claim 152, wherein X′

″

is selected from the group consisting of;

158. A compound as recited in claim 152, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

159. A compound as recited in claim 152, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys), where X′

″

≠

Y.

160. A compound as recited in claim 152, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile), where X′

″

≠

Y.

161. A chitosan-derivative compound for controlling microbial populations comprising:

162. A chitosan-derivative compound for controlling microbial populations comprising:

163. A compound as recited in claim 162, wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

164. A compound as recited in claim 162, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), praline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

165. A compound as recited in claim 162, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

166. A chitosan-derivative compound for controlling microbial populations comprising:

167. A chitosan-derivative compound for controlling microbial populations comprising:

168. A compound as recited in claim 167, wherein Z is selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

169. A compound as recited in claim 167 wherein Y is selected from the group consisting of:

ferrodoxin (desferroxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, formulations of hydroxy acids, fluorescein, Texas Red, rhodamine, Prodan, and cellular growth factors.

170. A compound as recited in claim 167, wherein Y is selected from the group consisting of:

lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

171. A compound as recited in claim 167, wherein Y is selected from the group consisting of:

tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

172. A method for synthesizing chitosan-arginine compounds comprising:

173. A method for synthesizing chitosan-arginine compounds comprising:

174. A method for synthesizing chitosan-derivative compounds comprising:

175. A method as recited in claim 174, and further comprising:

176. A method as recited in claim 175, wherein said R is arginine.

177. A method as recited in claim 174, wherein said R are unnatural amino acid compounds.

178. A method as recited in claim 177, wherein said unnatural amino acids are selected from the group consisting of 2,3-diaminopropionic acid;

2,4-diaminobutyric acid;

2,5-diaminopentanoic acid (ornithine) and their guanidinylated derivatives.

179. A method as recited in claim 175, wherein said R are acid-amine compounds.

180. A method as recited in claim 179, wherein said acid-amine compounds are selected from the group consisting of 2-amino-ethanoic acid, 3-amino-propanoic acid, 4-amino-butanoic acid, 5-amino-pentanoic acid, 6-amino-hexanoic acid and their guanidinylated derivatives.

181. A method as recited in claim 174, wherein said R are natural amino acid compounds.

182. A method as recited in claim 181, wherein said natural amino acid compounds are selected from the group consisting of serine (S), threonine (T), asparagine (N), glutamine (Q), tyrosine (Y), cysteine (C);

and those with nonpolar side chains glycine (G), alanine (A), valine (V), leucine (L), isoleucine (I), methionine (M), proline (P), phenylalanine (F) and tryptophan (W).

183. A method as recited in claim 175, wherein said R are co-derivatives of said chitosan-derivative compounds.

184. A method as recited in claim 183, wherein said co-derivatives are selected from the group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, polypeptides and chemical cellular growth factors.

185. A method as recited in claim 174, wherein said co-derivatives are selected from the group consisting of lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

186. A method as recited in claim 181, wherein said co-derivatives are selected from the group consisting of tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

187. A method as recited in claim 174 and wherein said R are salts of said chitosan-derivative compounds and said salts of co-derivatives of said chitosan-derivative compounds.

188. A method as recited in claim 187, wherein said salts are selected from the group consisting of chloride, hydroxide, phosphate, carbonate, acetate, lactate, citrate, cinnamate, oxalate, glutamate.

189. A method as recited in claim 174 wherein R is a guanidine derivative.

190. A method as recited in claim 189, wherein said derivative is selected from a group consisting of desferoxamine (desferrioxamine), alpha hydroxy acids, poly alpha hydroxy acids, retinol, alpha lipoic acid, flavinoids, coenzmye Q, Q10, fluorescein, Texas Red, rhodamine, Prodan, polypeptides and chemical cellular growth factors.

191. A method as recited in claim 189, wherein said derivative is selected from a group consisting of lysine (lys), histidine (his), aspartic acid (asp), glutamic acid (glu), alanine (ala), aspargine (asn), glutamine (gln), methionine (met), proline (pro), threonine (thr), serine (ser), tyrosine (tyr), and cysteine (cys).

192. A method as recited in claim 189, wherein said derivative is selected from a group consisting of tryptophan (trp), phenylalanine (phe), valine (val), leucine (leu) and isoleucine (ile).

193. A method for synthesizing chitosan-guanidine comprising:

194. A method for synthesizing chitosan-guanidine comprising:

195. A method as recited in claim 194, comprising synthesizing a guanidinylating agent: