IP Library › Granted Patent US 12,378,328
Granted Patent B2
US 12,378,328 · App. 17/267,271 · Granted Aug 5, 2025

Biohybrid peptidoglycan oligomers

Inventors: Xuewei Liu (Singapore, SG); Bee Eng Mary Chan (Singapore, SG); Hongwei Duan (Singapore, SG); Jingxi He (Singapore, SG); Kim Le Mai Hoang (Singapore, SG); Liang Yang (Singapore, SG)
Assignees: Nanyang Technological University; National University of Singapore
C08B37/003A61K47/542A61K47/61A61K47/64A61P31/04C12Q1/18
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Quick Facts
Patent No.
US 12,378,328
App. No.
17/267,271
Granted
Aug 5, 2025
Kind
B2
Abstract

The invention relates to a compound of formula Ia and/or formula Ib: or a pharmaceutically acceptable salt, solvate or prodrug thereof, where the groups are defined herein. The invention also relates to a pharmaceutical formulation comprising the compound for treating or detecting a microbial infection in a subject, a method of determining antimicrobial resistance of a microbial infection using the compound, and a method of determining an effective dose of one or more antimicrobial agents to kill a microorganism using the compound.

Claims (57)

1. A compound of formula Ia and/or formula Ib:

wherein:

R 1 represents C 1 to C 20 alkyl or —CH 2 CH(CO 2 H)OC 1-20 alkyl;

R 2 and R 3 each independently represent —C(═O)R 7 ;

R 4 to R 6 each represent H;

each R 7 independently represents C 1 to C 20 alkyl;

X 1 and X 2 independently represent -AA 1 -AA 2 -AA 3 -D-Ala-AA 4 , where:

AA 1 is selected from L -Ala, L -Gly, D -Gly or L -Ser;

AA 2 is selected from D -isoglutamate (γ- D -glutamate, γ- D -Glu), D -isoglutamine, or threo-3-hydroxyglutamate;

AA 3 is selected from L -homoserine, D -homoserine, D -5-hydroxylysine, D -Orn, L -Lys, D -Lys, L -Orn, L -2,4-diaminobutyrate, or L -5-hydroxylysine, where the amino group is functionalised to become a NHR 8 group and/or, where present, the hydroxyl group is functionalised to become a OR 8 group; and

AA 4 is selected from D -Ala, D -Ser or D -Lacate ( D -Lac),

at each occurrence R 8 is independently selected from one or more of H, a fluorescent group or a pharmaceutically active moiety,

n and m, and n′ and m′ are alternating repeating units, where n is from 5 to 100 and m is from 4 to 100, provided that m has the same value as n or is n−1 and n′ is from 5 to 100 and m′ is from 4 to 100, provided that m′ has the same value as n′ or is n′−1,

p or p′ are 1 or 0, or

a pharmaceutically acceptable salt, solvate or prodrug thereof.

2. The compound(s) according to claim 1 , wherein the compounds of formula Ia and Ib are Ia′ and Ib′, respectively

3. The compound(s) according to claim 1 , wherein:

when p and/or p′ is 1 and R 1 represents C 1 to C 20 alkyl, then R 8 represents a fluorescent group or a pharmaceutically active moiety; or

when p and/or p′ is 0 and R 1 represents —CH 2 CH(CO 2 H)OC 1-20 alkyl, then R 8 represents H.

4. The compound(s) according to claim 1 , wherein:

when p and/or p′ is 1, R 1 represents C 10 to C 15 alkyl; or

when p and/or p′ is 0, R 1 represents —CH 2 CH(CO 2 H)OC 10-15 alkyl.

5. The compound(s) according to claim 1 , wherein each R 7 independently represents C 1 to C 6 alkyl.

6. The compound(s) according to claim 1 , wherein:

AA 1 is selected from L -Ala, L -Gly, or L -Ser;

AA 2 is selected from D -isoglutamate (γ- D -glutamate, γ- D -Glu) or D -isoglutamine;

AA 3 is selected from L -Lys, D -Lys, L -Orn or L -2,4-diaminobutyrate, where the amino group is functionalised to become a NHR 8 group; and

AA 4 is selected from D -Ala or D -Ser.

7. The compound(s) according to claim 6 , wherein:

AA 1 is L -Ala;

AA 2 is D -isoglutamate (γ- D -glutamate, γ- D -Glu);

AA 3 is selected from L -Lys or L -Orn, where the amino group is functionalised to become a NHR 8 group; and

AA 4 is D -Ala.

8. The compound(s) according to claim 1 , wherein:

n is from 5 to 50 and m is from 4 to 50, provided that m has the same value as n or is n−1; and

n′ is from 5 to 50 and m′ is from 4 to 50, provided that m′ has the same value as n′ or is n′−1.

9. The compound(s) according to claim 1 , wherein when a R 8 group is a fluorescent group, it is selected from one or more of a rhodamine, a cyanine and a naphthalimide, where the point of attachment of the rhodamine, cyanine and naphthalimide to the rest of the molecule is through a SO 2 or C═O moiety.

10. The compound(s) according to claim 9 , wherein R 8 is selected from one or more of:

where the wavy line in each of the above moieties represents the point of attachment to the rest of the molecule.

11. The compound(s) according to claim 1 , wherein when a R 8 group is a pharmaceutically active moiety, it is selected from one or more of an antibiotic and an antigen moiety, where the point of attachment of the antibiotic and the antigen moiety to the rest of the molecule is through a SO 2 or C═O moiety.

12. The compound(s) according to claim 11 , wherein R 8 is selected from one or more of:

where the wavy line in each of the above moieties represents the point of attachment to the rest of the molecule.

13. The compound(s) according to claim 1 , selected from:

14. A pharmaceutical formulation comprising one or both of a compound of formula Ia and a compound of formula Ib as described in claim 1 and a pharmaceutically acceptable excipient, diluent or carrier.

15. A method of determining antimicrobial resistance of a microbial infection in a sample in vitro, the method comprising the steps of:

(A) contacting the sample with an antimicrobial to provide an antimicrobial sample;

(B) contacting the antimicrobial sample after a period of time with a compound of formula Ia and/or formula Ib as described in claim 1 where R 8 is a fluorescent group, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and

(C) detecting fluorescence produced by the fluorescent group upon exposure to a light source, wherein detection of fluorescence is used to determine antimicrobial resistance.

16. The method according to claim 15 , wherein the method is conducted in parallel or series, such that multiple samples are subjected to steps (A) to (C) with a plurality of individual antimicrobials and/or combinations of antimicrobials to determine the antimicrobial resistance profile of the microbial infection.

17. A method of determining an effective dose of one or more antimicrobial agents to kill a microorganism, the method comprising the steps of:

(iA) contacting one or more antimicrobial test solutions comprising one or more antimicrobial agents with the microorganism to provide one or more test samples, when there are two or more test samples, the concentration of each of the one or more antimicrobial agents is varied between the two or more antimicrobial test solutions to define a range;

(iB) contacting each of the one or more test samples after a period of time with a compound of formula Ia and/or formula Ib as described in claim 1 where R 8 is a fluorescent group, or a pharmaceutically acceptable salt, solvate or prodrug thereof; and

(iC) detecting fluorescence produced by the fluorescent group upon exposure to a light source in each of the test samples, wherein

detection of fluorescence in a test sample indicates the concentration of the one or more antimicrobial agents in said antimicrobial test solution is not effective, and the lack of detection of fluorescence indicates the concentration of the one or more antimicrobial agents in said antimicrobial test solution is effective, thereby determining the effective dose of the one or more antimicrobial agents.

18. A method of making a compound of formula Ia and/or formula Ib according to claim 1 , wherein the compound(s) is obtained and/or obtainable from a chitosan molecule comprising from 9 to 100 sugar units, such as from 10 to 50 sugar units.

19. A method of treatment of a microbial infection comprising administering a pharmaceutically effective amount of one or both of a compound of formula Ia and a compound of formula Ib as described in claim 1 where R 8 is a pharmaceutically active moiety, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject in need thereof.

20. A method of detecting a microbial infection in a subject comprising administering a pharmaceutically effective amount of one or both of a compound of formula Ia and a compound of formula Ib as described in claim 1 where R 8 is a fluorescent group, or a pharmaceutically acceptable salt, solvate or prodrug thereof, to a subject, subsequently exposing the subject to light irradiation and detecting a microbial infection by the presence of fluorescence.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded May 17, 2021
From: LIU, XUEWEI; CHAN, BEE ENG MARY; DUAN, HONGWEI; HE, JINGXI; LE MAI HOANG, KIM; YANG, LIANG
To: NANYANG TECHNOLOGICAL UNIVERSITY; NATIONAL UNIVERSITY OF SINGAPORE
Reel/Frame 056264/0160 →
Priority Claims (1)
SG 10201808123Y · Sep 18, 2019 · national
Continuity (1)
Related Publication 20220213232A1 · Jul 7, 2022
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