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Chrysophaentin analogs that inhibit FtsZ protein

A technology of compounds and compositions, applied in the field of antimicrobial compounds, capable of solving problems such as the rising prevalence of invasive infections

Inactive Publication Date: 2014-03-19
UNITED STATES OF AMERICA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In addition, the prevalence of invasive infections has been reported to rise as the number of patients infected with HIV, treated with cancer therapy, or treated with broad-spectrum antibiotics increases

Method used

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  • Chrysophaentin analogs that inhibit FtsZ protein
  • Chrysophaentin analogs that inhibit FtsZ protein
  • Chrysophaentin analogs that inhibit FtsZ protein

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Experimental program
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Embodiment 1

[0216] Compound Isolation and Structure Determination

[0217] Samples of the Chrysophaeum taylori algae were collected from 20 ft below the surface in Round Bay, St. John's Island (Lewis and Bryan, Am. J. Bot., 28:343, 1941). The algae, which is found growing in fluffy colonies on coarse sand or crushed coral substrates, exhibits a sulfur yellow color and can turn rusty brown within seconds when disturbed. The multicellular structure of C. taylori is extremely fragile, and the sticky cells are not well preserved. However, when freshly collected or freshly preserved (2.5% glutaraldehyde in seawater) samples were viewed under a light microscope, stalk-like structures consisting of branched slime "ribbons" of pyriform embedded cells could be seen. In addition, algae collections contained the known styrylchromone hormothamnione and showed remarkable similarities to field records published by Gerwick (J. Nat. Prod., 52:252, 1989) at all stages of manipulation.

[0218] Antimicro...

Embodiment 2

[0253]Antimicrobial tests of compounds 1, 1a, 4-8

[0254] Compounds 1-8 were tested against Staphylococcus aureus (SA, ATCC25923), methicillin-resistant Staphylococcus aureus (MRSA, ATCC BAA-41), Antimicrobial activity of multidrug-resistant Staphylococcus aureus (MDRSA, ATCC BAA-44), Enterococcus faecium (EF, ATCC49032), vancomycin-resistant Enterococcus faecium (VRE, ATCC700221) and Bacillus subtilis (ATCC49343). For the plate diffusion assay, agar plates inoculated with the bacterial suspension were prepared by adding 500 μL of the bacterial culture grown for 24 h to 100 mL of autoclaved and cooled to 55° C. Mueller Hinton II agar. The inoculated liquid agar (10 mL) was immediately transferred to a square petri dish and allowed to cool for 1 h. Control drugs for each microorganism included kanamycin (50 μg) for S. aureus and nitrofurantoin (25 μg) for MRSA. After incubation for 18 h at 37°C, the zone of inhibition was measured. The MICs of compounds 1 and 4-8 were deter...

Embodiment 3

[0262] GTPase activity and FtsZ polymerization

[0263] The bacterial cytoskeletal protein FtsZ is a GTPase and shares structural homology with the eukaryotic cytoskeletal protein tubulin, but lacks significant sequence similarity. FtsZ is essential for bacterial cell division. Non-cleavable GTP analogs have been reported to inhibit FtsZ in vitro, as do several small molecules. Inhibition of FtsZ terminates bacterial cell division and is a potent target for new antimicrobial agents. Compound 1 was tested for its ability to inhibit the GTPase activity of recombinant Escherichia coli FtsZ using a colorimetric assay that detects inorganic molybdenum released upon hydrolysis of GTP to GDP by complexation with molybdate (also known as malachite green). Phosphate (P i ). GTPase assay in 50mM MES, pH6.5, 50mM KCI, 5mMMgCl 2 in the presence of 2 μM FtsZ and different concentrations of compound 1. The solution was incubated at room temperature for 5 min before adding 0.25 mM GTP....

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Abstract

Embodiments of antimicrobial chrysophaentin compounds, pharmaceutical compositions including the chrysophaentin compounds, methods for using the chrysophaentin compounds, and methods for synthesizing the chrysophaentin compounds are disclosed. Certain embodiments of the chrysophaentin compounds inhibit FtsZ protein, thereby inhibiting the growth of clinically relevant bacteria, including drug-resistant strains.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of US Provisional Application No. 61 / 446,978, filed February 25, 2011, which is hereby incorporated by reference in its entirety. technical field [0003] The present disclosure generally relates to antimicrobial compounds and methods of their use. Background technique [0004] There is a continuing need to identify new lead compounds with novel mechanisms of action to treat infections caused by multidrug resistant bacteria. Infectious diseases are the leading cause of death worldwide, and it is estimated that in the United States, more people die from infections associated with methicillin-resistant Staphylococcus aureus (MRSA) than from HIV. In addition, the prevalence of invasive infections has been reported to rise as the number of patients infected with HIV, treated with cancer therapy, or treated with broad-spectrum antibiotics increases. In fact, 90,000 people die each year ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C15/50C07C17/266C07C25/24C07C41/05C07C43/275C07C43/285C07C43/295A61K31/085
CPCA61K31/055C07C39/373C07D321/00C07C37/14A61K31/085C07C43/23A61K45/06Y02A50/30
Inventor 卡罗勒·A·比利彼得·威普弗
Owner UNITED STATES OF AMERICA
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