Peptide-conjugated prodrugs
The present disclosure relates to a conjugated prodrug comprising a peptide conjugated to an antibiotic molecules via a cleavable linker and pharmaceutical compositions thereof. Also disclosed are methods of enhancing the intracellular concentration of an antibiotic agent in a bacterium and methods of treating a patient for a bacterial infection.
1 . A conjugated prodrug comprising:
a peptide comprising two to four amino acids, which peptide is conjugated to an antibiotic molecule via a cleavable linker, wherein:
(i) the peptide is selected from the group consisting of Gly-Gly, Gly-Gly-Gly, Gly-(D-Leu), Gly-(D-Ala), Gly-(D-Ser), Gly-Gly-Gly-Gly (SEQ ID NO: 1), Gly-Gly-(D-Phe), Gly-Gly-Phe, Gly-Phe-Gly, Gly-Gly-(D-Phe)-(D-Phe), Gly-Gly-Phe-Phe (SEQ ID NO: 3), Gly-Lys, and Gly-Asp;
(ii) the antibiotic molecule is not an aminoglycoside; and
(iii) wherein the cleavable linker forms an ester bond with the antibiotic molecule.
2 . The conjugated prodrug according to claim 1 , wherein the peptide is Gly-Gly-Gly-Gly (SEQ ID NO: 1), Gly-Gly-(D-Phe) (D-Phe), or Gly-Gly-Phe-Phe (SEQ ID NO: 3).
3 . The conjugated prodrug according to claim 1 , wherein the peptide is Gly-Gly, Gly-Gly-Gly, Gly-(D-Leu), Gly-(D-Ala), Gly-(D-Ser), Gly-Gly-(D-Phe), Gly-Gly-Phe, Gly-Phe-Gly, Gly-Lys, or Gly-Asp.
4 . The conjugated prodrug according to claim 1 , wherein the peptide is Gly-(D-Leu), Gly-(D-Ala), Gly-(L-Ser), Gly-Gly-(L-Phe), or Gly-Gly-(L-Phe)-(L-Phe).
5 . The conjugated prodrug according to claim 1 , wherein the peptide comprises a glycine residue covalently attached to the cleavable linker.
6 . The conjugated prodrug according to claim 1 , wherein the antibiotic molecule is selected from the group consisting of aminocoumarins, β-lactams, macrolides, ketolides, lincosamides, streptogramins, quinolones, rifamycins, tetracyclines, oxazolidinones, glycylcycline, amphenicals, and polymyxins.
7 . The conjugated prodrug according to claim 6 , wherein the antibiotic molecule is selected from the group consisting of chloramphenicol, N-(2-hydroxyacetyl)-ciprofloxacin, novobiocin, and benzylpenicillin (penicillin G).
8 . The conjugated prodrug according to claim 1 , wherein the antibiotic molecule is an efflux pump inhibitor.
9 . The conjugated prodrug according to claim 1 , wherein the cleavable linker is selected from the group consisting of:
—C(O)—(CH 2 ) n —C(O)— where n is an integer from 1 to 14,
—C(O)—(CH 2 ) m —CH═CH—C(O)— where m is an integer from 1 to 10,
—C(O)—CH—CH—C(O)—,
—C(O)-(1,2-cyclohexyl)-C(O)—,
—C(O)—Ar—C(O)— where Ar is a phenyl group, naphthyl group, or multi-ring aromatic group,
—C(O)—(CH 2 ) n —C(O)—(CH 2 ) q —C(O)—where n is an integer from 1 to 14 and q is from 1 to 10,
—C(O)—(CH 2 ) m —CH═CH—C(O)—(CH 2 ) q —C(O)—where m is an integer from 1 to 14 and q is from 1 to 10,
—C(O)—CH═CH—C(O)—(CH 2 ) q —C(O)—where q is an integer from 1 to 10,
—C(O)-(1,2-cyclohexyl)-C(O)—(CH 2 ) q —C(O)—where q is an integer from 1 to 10, and
—C(O)—Ar—C(O)—(CH 2 ) q —C(O)—where Ar is a phenyl group, naphthyl group, or multi-ring aromatic group and q is an integer from 1 to 10.
10 . The conjugated prodrug according to claim 1 , which is selected from the group consisting of:
wherein n is an integer from 1 to 14, q is an integer from 1 to 10, and Z is the peptide.
11 . The conjugated prodrug according to claim 10 , wherein the peptide comprises a glycine residue covalently attached to the cleavable linker.
12 . The conjugated prodrug according to claim 1 , wherein the cleavable linker is —C(O)—(CH 2 ) n —C(O)—, where n is an integer from 1 to 14.
13 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a conjugated prodrug according to claim 1 .
14 . A method of enhancing intracellular concentration of an antibiotic agent in a bacterium, the method comprising:
contacting a bacterium with an effective amount of the conjugated prodrug according to claim 1 , whereby said conjugated prodrug is taken up by the bacterium and said linker is cleaved intracellularly to release the antibiotic agent from said prodrug, causing an increase in the intracellular concentration of the antibiotic agent.