Fabi inhibitors for gram-negative pathogens
AssigneesThe Board of Trustees of the University of Illinois, The General Hospital Corporation, The Broad Institute, Inc.
InventorsPaul J. HERGENROTHER, Erica Nicole PARKER, Deborah HUNG, Michael SERRANO-WU, Katie Kyungae LEE
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Abstract
A FabI inhibitor called fabimycin that has impressive activity against >200 clinical isolates of E. coli, K. pneumoniae, and A. baumannii. Fabimycin has activity in multiple mouse models of infection caused by Gram-negative bacteria, including a model of urinary tract infection. Fabimycin has translational promise, and its discovery provides data indicating that antibiotics whose spectrum of activity is restricted to Gram-positive bacteria can be systematically modified to accumulate in Gram-negative bacteria and be effective against these problematic pathogens.
Claims24
A compound of Formula I or II:
- or a salt thereof;
- wherein
- G1 is —CH(C0-C6)alkyl-NH2, CH2, —CH(C3-C6)cycloalkyl-NH2, —CHN(H)(C2-C6)alkyl-NH2, or G2;
- G2 is
- wherein G3 is NH, —CH(C0-C6)alkyl-NH2, or —CH2CH(C0-C6)alkyl-NH2;
- J is —(CH2)m—;
- and
- m is 1-3;
- Q is CHRa, NH, —NHCH2—, —CH2CH2—, —C(═O)N—, or absent, wherein Ra is H or halo;
- X is C═O or CH2;
- R1 is H or halo;
- R2 is —(C1-C6)alkyl, H, or —(C1-C6)alkyl-NH2;
- R3 is H or —(C1-C6)alkyl-NH2;
- and
- R4 is methyl, ethyl, propyl, butyl, pentyl, hexyl, or —(C3-C6)cycloalkyl;
- wherein for Formula I, R2 and R4 taken together optionally form a heterocycle;
- and
- wherein at least one of G1, R2, or R3 comprises an amine moiety and each alkyl moiety is optionally substituted.
A compound of Formula III:
- or a salt thereof;
- wherein
- R3 is H or —(C1-C6)alkyl;
- R6 is
- wherein R1 is H or halo, and n is 1-4;
- and
- R7 is H or —(C0-C6)alkyl-NH2.
A compound of Formula IV:
- or a salt thereof;
- wherein
- G4 is O, NH, CH2, —CH(C0-C6)alkyl-NH2, —N(C═O)(C1-C6)alkyl-NH2;
- X is C═O or CH2;
- R1 is H or halo;
- R2 is H, —(C1-C6)alkyl, or —(C1-C6)alkyl-NH2;
- R3 is H or —(C1-C6)alkyl-NH2;
- and
- R4 is methyl, ethyl, or propyl;
- wherein at least one of G4, R2, or R3 comprises an amine moiety.
(canceled)
24-27. (canceled)
Dependencies are inferred from the claim text.