Anti-bacterial agents based upon oxoanion binding

Details Anti-bacterial agents based upon oxoanion binding Anti-bacterial agents based upon oxoanion binding

2002-08-22

2004-05-18

Weddington, Kevin E (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Boron containing doai

Reexamination Certificate

active

06737415

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compositions and methods for controlling bacterial growth, and more particularly to anti-bacterial agents and their methods of use.
2. Description of the Related Art
Bacterial infections remain a public health concern, and indeed a growing one in view of increasing resistance to existing drugs by pathogenic bacteria. Drugs now in use fall into a relatively small number of chemical classes, and operate by one of a relatively small number of mechanisms. Development of resistance to one drug can therefore adversely affect the efficacy of others. Moreover, because bacteria can exchange genetic information, resistance can spread from one species to another.
It is therefore desirable to have new classes of anti-bacterial agents based upon novel mechanisms of action, to which bacteria are unlikely to have resistance.
In addition, bacteria in nature commonly grow attached on solid surfaces in a mode of growth referred to as a biofilm. Bacteria within biofilms differ physiologically from those grown in liquid culture (planktonic cells) in having increased resistance to environmental stresses (such as antibiotic treatment). In clinical environments, biofilms of pathogenic bacteria lead to persistent and chronic infections refractory to treatment with conventional antibiotics. The U.S. Centers for Disease Control estimate that 60% of bacterial infections involve such biofilms. Industrially, biofilms contaminate and clog water lines, foul surfaces and contribute to corrosion and decay. Not all the consequences of biofilm formation are deleterious, however; for example, in bioproduction processes biofilms help in maintaining a stable population of cells as substrate passes through a bioreactor.
Consequently it is desirable not only to have new classes of anti-bacterial agents, but also to have ways of promoting and/or inhibiting the formation and maintenance of bacterial biofilms.
SUMMARY OF THE INVENTION
A preferred embodiment provides a method of controlling bacterial growth, comprising exposing a bacterium to a compound of structure I
wherein E is selected from the group consisting of B, P, and S, T
1
, and T
2
are each independently selected from the group consisting of O, NR, and CH
2
, where R=H or C
1
-C
8
alkyl, or C
1
-C
8
oxoalkyl, and L is selected from the group consisting of ethylene, propylene, and four to six-membered alicyclic and aromatic rings, provided that structure I does not include AI-2-borate. Preferably, E is B (boron) or P (phosphorous). Preferably, T
1
, and T
2
are O (oxygen). Preferably, the compound has a molecular weight less than about 750 Da, more preferably, less than about 500 Da. In preferred embodiments, bacterial growth is controlled by administering a therapeutically effective amount of the compound to a human infected with the bacterium.
Another preferred embodiment provides a pharmaceutical composition comprising a compound having structure I
wherein E is selected from the group consisting of B, P, and S, T
1
and T
2
are each independently selected from the group consisting of O, NR, and CH
2
, where R=H or C
1
-C
8
alkyl, or C
1
-C
8
oxoalkyl, and L is selected from the group consisting of ethylene, propylene, and four to six-membered alicyclic and aromatic rings, provided that structure I does not include AI-2-borate. Preferably, L is tetrahydrofuran bearing a keto, a hydroxy, and a carboxamido functional group, T
1
and T
2
are oxygen, and E is B or P. More preferably, the compound has the following structure:
These and other embodiment are described in greater detail below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Preferred embodiments provide pharmaceutical compositions comprising compounds having the structure I:
wherein E is selected from the group consisting of B, P, and S, T
1
, and T
2
are each independently selected from the group consisting of O, NR, and CH
2
, where R=H or C
1
-C
8
alkyl, or C
1
-C
8
oxoalkyl, and L is selected from the group consisting of ethylene, propylene, and four to six-membered alicyclic and aromatic rings, provided that structure I does not include AI-2-borate.
Preferred L groups include ethylene, propylene, cyclopentyl, cyclohexyl, pyrrolidine, tetrahydrofuran, piperidine, pyran, dioxane, morpholine, pyrrole, furan, pyridine, pyrimidine, pyrazine, imidazole, thiazole, oxazole, purine, and indazole. Particularly preferred L groups include ethylene, propylene, cyclopentyl, cyclohexyl, pyrrolidine, tetra-hydrofuran, piperidine, pyran, dioxane, and morpholine. Most preferred L groups include cyclopentyl, cyclohexyl, pyrrolidine, tetrahydrofuran, piperidine, pyran, dioxane, and morpholine. A particularly preferred compound has the structure II, where E is B or P:
Other specific examples of preferred compounds include cyclic borate, sulfate, or phosphate esters and amides, as shown below for compounds derived from [3.3.0] bicyclooctane:
The unsubstituted five-membered ring in the above structures can incorporate one or more heteroatoms, with hydrogen-bonding heteroatoms such as O and N being particularly preferred. The unsubstituted five-membered ring in the above structures can also bear one or more substituents containing heteroatoms, again with hydrogen-bonding heteroatoms such as O and N being particularly preferred.
Additional preferred embodiments include compounds derived from [3.4.0] bicyclononane. Specific examples include the following:
Compounds having hydrogen-bonding substituents at a bridgehead position are also particularly preferred, in view of the strong H-bonding to this position evident in the structure found for the luxP-AI-2 co-crystal (discussed below). Examples of such compounds include the following, with R=OH or NH
2
being particularly preferred:
Methods of making various specific compounds are described in the Examples below. Methods of making the other compounds described herein may be undertaken by modifying the syntheses described in the Examples below in a manner known to those skilled in the art.
Specific compounds for a particular application are preferably selected with the aid of computer-aided drug design and/or combinatorial chemistry methods that are well-known to those skilled in the art. Computers and software suitable for carrying out computer-aided drug design are commercially available. Preferred computer packages include Sybyl version 6.8 from Tripos, Inc. and MacroModel version 8.0 from Schrodinger Software. Preferably, the heteroatoms are spatially disposed to interact with hydrogen-bonding groups on the LuxP protein.
One application of the present invention is in influencing the development or maintenance of biofilms, communities of bacteria that grow attached to solid surfaces. Bacteria within biofilms often exhibit greater resistance to antibiotic treatment than those living freely, and hence commonly lead to persistent and chronic infections refractory to treatment. The U.S. Centers for Disease Control estimate that 60% of bacterial infections involve such biofilms. Industrially, biofilms contaminate and clog water lines, foul surfaces and contribute to corrosion and decay. Not all the consequences of biofilm formation are deleterious, however; for example, in bioproduction processes biofilms help in maintaining a stable population of cells as substrate passes through a bioreactor.
Quorum-sensing influences biofilm formation, and therefore ways of promoting or impeding quorum-sensing also provide ways of controlling biofilm formation, including biofilm growth. For example, compounds of structure I can be used to affect biofilms by either stimulating their formation or hindering it. Methods for promoting or impeding biofilm formation are preferably practiced by exposing the bacteria to the compound in an amount that affects biofilm formation. Particular amounts for a given application may be determined by routine experimentation in a manner generally known to those skilled in the art.
Reference to a particular com

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