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Compositions and methods for treating microbial infections

a technology for microbial infections and compositions, applied in the field of treatment of microbial infections, can solve the problems of preventing the identification of small molecules that target pathways, unable to identify candidate therapeutics, and a huge threat,

Inactive Publication Date: 2015-06-25
VANDERBILT UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent text describes a new approach to treating microbial infections by targeting the central metabolic pathways of pathogens. The invention is based on the discovery of small molecule screening strategies that have not identified candidate therapeutics that target central metabolism. The technical effect of the invention is to provide compounds that can increase intracellular heme levels, which profoundly impacts respiration of the pathogens and can lead to the development of new antibiotics that target central metabolism. The invention has been supported by the National Institutes of Health.

Problems solved by technology

The rapidly increasing resistance of pathogenic bacteria to all relevant antimicrobials is a tremendous threat to global public health and has galvanized efforts focused on uncovering new targets for therapeutic intervention.
However, these screening strategies have prevented the identification of small molecules that target pathways conditionally required during infection.
However, despite the tremendous therapeutic potential, small molecule screening strategies based on growth inhibition have not identified candidate therapeutics that target central metabolism.

Method used

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  • Compositions and methods for treating microbial infections
  • Compositions and methods for treating microbial infections
  • Compositions and methods for treating microbial infections

Examples

Experimental program
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Effect test

example 1

[0106]Like most bacteria, S. aureus requires iron to successfully infect its host. Iron is a cofactor for essential enzymes involved in host defense, DNA replication, and energy production. In humans most iron is found in the form of heme. S. aureus preferentially uses host heme as an iron source during infection (72). It does this using the iron-regulated surface determinant (Isd) system to import heme into the cell (79). In the cytoplasm heme can either be used intact as a cofactor or degraded to release free iron. In addition to stealing host heme, S. aureus can synthesize heme de novo.

[0107]Despite being an essential part of staphylococcal biology, heme is toxic. With reference to FIG. 1, bacterial gene regulation is controlled by a number of signal transduction systems known as two-component regulatory systems (TCS) (1-7). The present inventors identified a novel TCS in many Gram positive pathogens that responds to alterations in available heme, a critical cofactor of bacterial...

example 2

[0122]The structure, purity, and heme-activating properties of '882 were verified following its resynthesis by way of a five-step reaction sequence starting from commercially available 1-hydroxy-2-naphthaldehyde (44).

Synthesis and Relative HssRS Activation of Analogues '8882(1)

[0123]Both purchased and resynthesized '882 equally maintain HssRS activation. Moreover, the free base of '882 and its corresponding trifluoroacetate salt demonstrate good chemical stability, have no rule of five violations, and exhibit good solubility in DMSO and aqueous solution (45). Using an iterative medicinal chemistry approach, preliminary structure activity relationship (SAR) data has been collected (summarized above). The identification of positions around the '882 scaffold that tolerate structural modification is useful in the development of an affinity-probe derived from '882.

[0124]Analogs of '882 were divided into two classes, and chemical modifications of both the Western-naphthol ring and the Eas...

example 3

[0126](Prophetic, in part)—Sensor probe based on an '882 scaffold.

[0127]Based on the SAR data of '882, the present inventors propose the design of chemical probes for the purpose of target identification. Probes are prepared and examined in the context of affinity chromatography and photoaffinty labeling strategies (48-50). The former approach will rely on streptavidin chromatography in conjunction with immobilization of the biotin conjugate 5. Boc-protected pyrazole 3 have been prepared and it has been determined that 3 activates HssRS as measured by XylE assay. The present inventors are now working toward PEG-linked Boc-protected amine 4. Treatment of 4 with trifluoroacetic acid, followed by condensation with biotin will afford conjugate 5 ready for affinity chromatography experiments.

[0128]In addition to affinity chromatography a series of photoaffinity probes will be designed, prepared, and evaluated (51). Key elements of photoaffinity ligand (PAL) design are selection of a phot...

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Abstract

Embodiments of the presently-disclosed subject matter include activators of HssRS that induce endogenous heme biosynthesis by perturbing central metabolism. These molecules are toxic to fermenting S. aureus, including clinically relevant small colony variants (SCVs). The utility of targeting fermenting bacteria is exemplified by the fact that this compound prevents the emergence of antibiotic resistance, enhances phagocyte killing, and reduces S. aureus pathogenesis. This small molecule is a powerful tool not only for studying bacterial heme biosynthesis and central metabolism, but also establishes targeting of fermentation as a viable antibacterial strategy.

Description

GOVERNMENT INTEREST[0001]This invention was made with government support under U54 AI057157-06, AI073843, T32 HL069765, and AI069233, each awarded by National Institutes of Health. The government has certain rights in the invention.TECHNICAL FIELD[0002]The presently-disclosed subject matter relates to treatment of microbial infections. In particular, the presently-disclosed subject matter relates to fermentation inhibitors and the treatment of microbial infections.INTRODUCTION[0003]The rapidly increasing resistance of pathogenic bacteria to all relevant antimicrobials is a tremendous threat to global public health and has galvanized efforts focused on uncovering new targets for therapeutic intervention. In the past, the most successful antibiotic development strategies have exploited bacterial systems that are absolutely required for growth in culture. However, these screening strategies have prevented the identification of small molecules that target pathways conditionally required...

Claims

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Application Information

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IPC IPC(8): A61K31/519A61K31/415A61K31/4439A61K45/06C12Q1/18C07D487/04C07D401/04C07D409/04C07D231/12A61K31/4155C07D405/04
CPCA61K31/519A61K31/4155A61K31/415A61K31/4439A61K45/06C12Q1/18C07D487/04C07D401/04C07D409/04C07D231/12C07D405/04C07D495/04A61K31/7008A61P31/04
Inventor SKAAR, ERIC P.ANZALDI, LAURASULIKOWSKI, GARYWATERSON, ALEXREID, PAUL
Owner VANDERBILT UNIV
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