Nitric oxide-releasing polyaminoglycosides as biodegradable antibacterial scaffolds and methods pertaining thereto

Patent metadata

Field	Value
Publication number	US-11723914-B2
Application number	US-201816497696-A
Country	US
Kind code	B2
Filing date	Mar 28, 2018
Priority date	Mar 28, 2017
Publication date	Aug 15, 2023
Grant date	Aug 15, 2023

Abstract

Provided herein are hyperbranched polyaminoglycosides, where in some embodiments, the hyperbranched polyaminoglycosides are covalently modified to store and release nitric oxide. Some embodiments pertain to methods of making and use of hyperbranched polyaminoglycosides. In some embodiments, the covalently modified hyperbranched polyaminoglycosides may be tailored to release nitric oxide in a controlled manner and are useful for eradication of both gram positive and gram negative bacteria as well as other microbes.

First claim

That which is claimed:

1. A hyperbranched polyaminoglycoside, comprising a first aminoglycoside unit comprising Formula II:

wherein each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 9 , and R 10 is independently selected from —H or represents a covalent bond to one or more linking units;
wherein a linking unit of the one or more linking units is represented by the following structure:

wherein at least one linking unit forms a covalent bridge between the first aminoglycoside unit and a second aminoglycoside unit; and
wherein at least one aminoglycoside unit of the hyperbranched polyaminoglycoside is derived from kanamycin;
wherein at least one aminoglycoside unit of the hyperbranched polyaminoglycoside comprises one or more terminal units selected from:

and
wherein at least a secondary amine of the hyperbranched polyaminoglycoside comprises a N-diazeniumdiolate NO donor.

2. The hyperbranched polyaminoglycoside of claim 1 , additionally comprising one or more dendritic units having the structure:

where “—N-aminoglycoside” represents the structure of Formula II.

3. The hyperbranched polyaminoglycoside of claim 1 , additionally comprising one or more linear units having the structure:

where “—N-aminoglycoside” represents the structure of Formula II.

4. The hyperbranched polyaminoglycoside of claim 1 , wherein at least one secondary amine of the hyperbranched polyaminoglycoside comprises a NO donor.

5. The hyperbranched polyaminoglycoside of claim 1 , wherein the hyperbranched polyaminoglycoside has a number average molecular weight of less than or equal to about 4 kDa.

6. The hyperbranched polyaminoglycoside of claim 1 , wherein the hyperbranched polyaminoglycoside has a weight average molecular weight of less than or equal to about 7 kDa.

7. The hyperbranched polyaminoglycoside of claim 1 , wherein the hyperbranched polyaminoglycoside has a NO storage capacity of greater than or equal to about 0.4 μmol NO/mg hyperbranched polyaminoglycoside.

8. The hyperbranched polyaminoglycoside of claim 1 , wherein the hyperbranched polyaminoglycoside provides greater than or equal to about 99% bacterial reduction in a bacterial viability assay performed under static conditions over 2 hours against one or more of P. aeruginosa, S. aureus P. gingivalis, A. actinomycetemcomitans, A. viscosus , and/or S. mutans at a concentration of less than or equal to about 2 mg/mL.

9. A hyperbranched polyaminoglycoside, comprising a first aminoglycoside comprising a structure of Formula I:

wherein G 1 is selected from the group consisting of:

wherein G 2 is selected from the group consisting of:

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are independently selected from the group consisting of —H, optionally substituted C 1 -C 6 alkyl, optionally substituted polyamino having 1 to 6 repeat units with intervening C 1 -C 6 alkyl groups, optionally substituted polyether having 1 to 6 repeat units with intervening C 1 -C 6 alkyl groups, and a covalent bond to a linking unit;
X a , X b , and X c are independently selected from —H, —OH, and C 1 -C 6 alkyl;
wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 is a covalent bond to one or more linking unit selected from the group consisting of:

wherein “ ” indicates an attachment to the first aminoglycoside;
W 1 , W 2 , or W 3 , where present, are independently selected from one or more additional aminoglycosides or one or more end-capping substituents and at least one linking unit provides a covalent bridge from the first aminoglycoside to a second aminoglycoside;
R a , R b , and R c are independently selected from the group consisting of optionally substituted C 1 -C 6 alkyl, optionally substituted polyamino having 1 to 6 repeat units (with C 1 -C 6 alkyl(s)), or optionally substituted polyether having 1 to 6 repeat units (with C 1 -C 6 ) alkyl(s)); and
wherein the one or more end-capping substituents, where present, independently have a formula of —NH—((CH 2 ) a X 1 ) b —(CH 2 ) c H where X 1 is O or NH and a, b, and c are independently an integer from 0 to 10, and
wherein said hyperbranched polyaminoglycoside further comprises a NO-donating group, and
wherein at least one aminoglycoside unit of the hyperbranched polyaminoglycoside comprises one or more terminal units selected from:

10. The hyperbranched polyaminoglycoside of claim 9 , wherein the first aminoglycoside comprises a structure of Formula II:

11. The hyperbranched polyaminoglycoside of claim 9 , wherein the first aminoglycoside comprises a structure of Formula III:

12. The hyperbranched polyaminoglycoside of claim 9 , wherein the NO donating group is selected from the group consisting of:

where “ ” indicates attachment to other atoms within the hyperbranched aminoglycoside.

13. A method of decreasing microbial contamination comprising,
contacting a surface contaminated with a plurality of microbes with the hyperbranched polyaminoglycoside of claim 1 ;
wherein the nitric oxide donor generates nitric oxide and induces damage to the membrane and/or DNA of the microbes, thereby reducing the number of viable microbes.

14. A pharmaceutical formulation comprising:
the hyperbranched polyaminoglycoside of claim 1 ; and
a pharmaceutically acceptable carrier.

15. A method of delivering nitric oxide to a subject, comprising:
administering an effective amount of the hyperbranched polyaminoglycoside of claim 1 to reduce infection or bacterial load in the subject.

Assignees

• Univ North Carolina Chapel Hill

Inventors

• Schoenfisch Mark H
• Yang Lei

Classifications

• A61K31/726 Primary

  Glycosaminoglycans, i.e. mucopolysaccharides (chondroitin sulfate, dermatan sulfate A61K31/737) · CPC title

• A01N43/16

  with oxygen as the ring hetero atom · CPC title

• A01N59/00

  Biocides, pest repellants or attractants, or plant growth regulators containing elements or inorganic compounds · CPC title

• A61K31/7036

  having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins · CPC title

• A61K47/595

  Polyamides, e.g. nylon (polyamino acids A61K47/62) · CPC title