US 2003/0199516 A1Published application

Methods of treating infection by drug resistant bacteria

AssigneeGenesoft, Inc.

InventorsHeinz E. Moser, Eldon E. Baird, Roland W. Burli, Yigong Ge, Sarah White

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Abstract

Methods are provided for treating an infection by Gram-positive bacteria in a mammal, by administering to the mammal an effective amount of a compound that binds noncovalently in the minor groove of duplex DNA, the compound being identified by a number of DNA binding parameters and, in many instances, being a polyaromatic compound.

Claims26

Dependent claims

A method for treating an infection by Gram-positive bacteria in a mammal, said method comprising administering to said mammal an effective amount of a compound that binds noncovalently in the minor groove of duplex DNA, which compound:

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of:
(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(l) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
and
(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
ii) exhibits a MIC of less than or equal to 2 μg/mL against at least one of Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus ATCC 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422;
iii) exhibits a MIC of greater than or equal to 32 μg/mL against Candida albicans ATCC 38247;
and
iv) has a molecular weight of from 100 to about 1100.

14 more elements

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of:
(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(f) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
and
(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
ii) has activity ratio X/Y equal to or greater than 16, wherein X is the MIC of the compound against Candida albicans ATCC 38247 and Y is the lowest MIC of the compound from among the MIC's for Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422;
and
iii) has a molecular weight of from 100 to about 1100.

13 more elements

A compound useful for the treatment of an infection by Gram-positive bacteria, said compound having the formula:

A-((L1)p-Ar1)n-L1-B (I)
wherein
A is member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;
the subscript n is an integer of from 2 to 7;
the subscript p in each instance is an integer of from 0 to 1, indicating the presence or absence of each linking group (L1);
L1 is a linking group in which the superscript i is an integer of from 1 to n, and each linking group can be the same or different from the other linking groups and is selected from the group consisting of —NH—, —CONH—, —SO2NH—, —CONR—, —SO2NR—, (C1-C6)alkylene, (C1-C6)heteroalkylene, and combinations thereof;
Ari is a substituted or unsubstituted aryl or heteroaryl group, in which the superscript i is an integer of from 1 to n and denotes the position away from A that is occupied by each aryl or heteroaryl group, and each Ar group can be the same or different from any other Ar group;
Lx is a linking group selected from —CONH—, —SO2NH—, —CONR—, —SO2NR—, (C1-C6)alkylene, (C1-C6)heteroalkylene, and combinations thereof;
and
B is a member selected from the group consisting of a substituted or unsubstituted aryl or heteroaryl group, a substituted or unsubstituted heterocyclic group, an amino group and a mono- or di-alkyl amino group;
or a pharmaceutically acceptable salt, prodrug form or protected form thereof;
wherein said compound
i) binds with a dissociation constant of equal to or less than 100 nM to at least one of:
(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(f) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
and
(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
ii) has activity ratio X/Y equal to or greater than 16, wherein X is the MIC of the compound against Candida albicans ATCC 38247 and Y is the lowest MIC of the compound from among the MIC's for Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422;
and
iii) has a molecular weight of from 100 to about 1100.

25 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/244,142Filed 12 Sep 2002
Priority: 13 Sep 2001
Published: 23 Oct 2003
Term ends: Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles

Family

Application60/322,704Us provisional application · filed 13 Sep 2001
US 2003/0199516 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

i) binds with a dissociation constant of equal to or less than 100 nM to at least one of:
(a) a target sequence AAAAAGCAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(b) a target sequence AAAAAGACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(c) a target sequence AAAAAGTACAAAAA in the 351 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. I;
(d) a target sequence AGTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(e) a target sequence AATACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(l) a target sequence ATTACT in the 310 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. II;
(g) a target sequence TGACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(h) a target sequence GACAATTAATCA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(i) a target sequence AATTAATCAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
(j) a target sequence ACAATTA in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
and
(k) a target sequence ACAATTAAT in the 352 base pair EcoRI/PvuII restriction fragment of a polynucleotide of SEQ ID NO. III;
ii) exhibits a MIC of less than or equal to 2 μg/mL against at least one of Enterococcus faecium ATCC 51559, Staphylococcus aureus ATCC 27660, Staphylococcus aureus ATCC 33591, Staphylococcus aureus ATCC 43300, and Streptococcus pneumoniae ATCC 51422;
iii) exhibits a MIC of greater than or equal to 32 μg/mL against Candida albicans ATCC 38247;
and
iv) has a molecular weight of from 100 to about 1100.

14 more elements

Facts

Application

10/244,142Filed 12 Sep 2002

Priority

13 Sep 2001

Published

23 Oct 2003

Term ends

Not estimatedThe source records don’t support an estimate.

Classification20 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/381
Having sulfur as a ring hetero atom: having five-membered rings
A61K 31/4178
1,3-Diazoles: not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
A61K 31/4196
Having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole: 1,2,4-Triazoles