Cleavable conjugates of antibiotics and an antibacterial cell-penetrating peptide

1. A method of treating a microbial infection in a patient, wherein the method comprises administering to the patient a pharmaceutical composition comprising a compound of formula:

a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or derivative thereof,

wherein

R 1 is an antibiotic moiety;

R 2 and R 3 are each independently H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

R 4 is H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

L 3 is C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

Z is a linker comprising a disulfide bond (S—S bond); and

n is 3-8, wherein the microbial infection is an infection caused by pathogen S. aureus, S. epidermidis, P. aeruginosa, A. baumannii, K. pneumoniae, E. faecium , enterobacteriaceae, or any combination thereof.

2. The method of claim 1 , wherein the compound is:

or a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or a derivative thereof,

wherein

R 1 is an antibiotic moiety;

R 2 and R 3 are each independently H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

R 4 is H, a C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

L 1 , L 2 , L 3 are each independently C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl;

X is O or NR 5 , wherein R 5 is H, C 1 -C 8 branched or unbranched alkyl chain, or a C 3 -C 8 cyclic alkyl, or X combined with R 1 together is an antibiotic moiety; and

n is 3-8.

3. The method of claim 1 , wherein R 1 or R 1 —X represents the moiety of an aminoglycoside antibiotics or any derivative thereof.

4. The method of claim 1 , wherein R 1 or R 1 —X represents an antibiotic moiety, wherein the antibiotic moiety is of an antibiotics selected from the group consisting of Gentamicin, Streptomycin, Kanamycin, Fradiomyctn, Paromomycin, Tobramycin, Netilmicin, Amikacin, Neomycin, Ribostamycin, Dibekacin, Sisomicin, Isepamicin, Bekanamycin, Astromicin, Plazomicin, Vancomycin, Linezolid, Erythromycin, Eperezolid, and any derivative thereof.

5. The method of claim 1 , wherein R 2 and R 3 are each independently C 1 -C 4 branched or unbranched alkyl chain.

6. The method of claim 1 , wherein R 2 and R 3 are isobutyl group.

7. The method of claim 1 , wherein R 4 is hydrogen.

8. The method of claim 2 , wherein L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—.

9. The method of claim 1 , wherein R 1 represents an antibiotic moiety, and the antibiotic moiety is of an antibiotics selected from the group consisting of Gentamicin, Streptomycin, Kanamycin, Fradiomyctn, Paromomycin, Tobramycin, Netilmicin, Amikacin, Neomycin, Ribostamycin, Dibekacin, Sisomicin, Isepamicin, Bekanamycin, Astromicin, Plazomicin, Vancomycin, Linezolid, Erythromycin, Eperezolid, and any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.

10. The method of claim 2 , wherein R 1 or R 1 —X represents an aminoglycoside antibiotics moiety, and the aminoglycoside antibiotics is selected from the group consisting of Gentamicin, Kanamycin, Tobramycin, Amikacin, Neomycin, Plazomicin, and any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.

11. The method of claim 2 , wherein R 1 or R 1 —X represents Kanamycin moiety or any derivative thereof; R 2 and R 3 are isobutyl group; R 4 is hydrogen; L 1 is —(CH 2 ) 3 —, L 2 is —(CH 2 ) 3 —, and L 3 is —(CH 2 )—; X is O; and n is 4.

12. The method of claim 1 , wherein the compound is:

a stereoisomer, tautomer, solvate, pharmaceutically acceptable salt, or a derivative thereof.

13. The method of claim 1 , wherein the microbial infection is a biofilm infection.

14. The method of claim 1 , wherein the microbial infection is an infection caused by pathogen S. aureus (ATCC 6538), S. aureus (USA400), S. epidermidis (ATCC 35984), P. aeruginosa (PAO1), P. aeruginosa (1109), A. baumannii (BAA-1605), K. pneumoniae (BAA-1706), E. faecium (ATCC 700221) or any combination thereof.