Inhibitors of bacterial type III secretion system
Inventors
Moir, Donald T. • Aiello, Daniel • Peet, Norton P. • Williams, John D.
Assignees
Publication Number
US-8906945-B2
Publication Date
2014-12-09
Expiration Date
2030-04-06
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Abstract
Organic compounds showing the ability to inhibit effector toxin secretion or translocation mediated by bacterial type III secretion systems are disclosed. The disclosed type III secretion system inhibitor compounds are useful for combating infections by Gram-negative bacteria such as Salmonella spp., Shigella flexneri, Pseudomonas spp., Yersinia spp., enteropathogenic and enteroinvasive Escherichia coli, and Chlamydia spp. having such type III secretion systems.
Core Innovation
The invention provides new organic compounds that are capable of inhibiting the type III secretion system (T3SS) found in Gram-negative bacteria. These T3SS inhibitor compounds were identified through high throughput bioluminescent reporter assays using Pseudomonas aeruginosa, and further validated using secondary assays for T3SS-mediated effector secretion and translocation. The compounds specifically inhibit T3SS-mediated secretion of effector toxins from bacterial cells and, in preferred embodiments, also prevent the translocation of these effectors into host cells.
Several specific compounds are disclosed, including various phenoxyacetamide inhibitors such as MBX 1641 and its R-stereoisomer MBX 1684, which exhibit selective and potent inhibition of T3SS-mediated secretion and translocation in bacterial cells, particularly P. aeruginosa, Yersinia pestis, and Chlamydia trachomatis. The invention also details structural classes of inhibitors and describes their in vitro activity, minimal cytotoxicity to mammalian cells, and lack of effect on bacterial growth or type II secretion.
The invention addresses the need for new, potent inhibitors of bacterial T3SS, especially in the context of increasing drug resistance and the insufficiency of conventional antibiotics to combat serious infections caused by P. aeruginosa and related pathogens. By inhibiting a major virulence mechanism without inhibiting bacterial growth directly, these T3SS inhibitors provide a new therapeutic strategy aimed at supporting the host immune defense or functioning as adjunctive agents with traditional antibiotics.
Claims Coverage
There is one independent claim in the patent, which outlines the main inventive features relating to the treatment of infections using specific T3SS inhibitors.
Method for treating an individual infected with a Gram-negative bacterium using specific T3SS inhibitor compounds
A method that comprises administering to an individual infected with a Gram-negative bacterium an effective amount of a compound selected from a specific group of organic molecules. These compounds are characterized by their ability to inhibit T3SS-mediated effector secretion. The method covers: - Use of a compound from a described group such as MBX 1641, MBX 1684, compound 3, compound 4, compound 5685325, compound 6380194, compound 6430631, compound 7247834, compound F5054-0019, and combinations thereof. - Applicability of the method to human individuals. - Applicability to Gram-negative bacteria of the genus Pseudomonas, Salmonella, Yersinia, or Chlamydia, specifically including Pseudomonas aeruginosa, Yersinia pestis, or Chlamydia trachomatis. - Optionally administering an additional active ingredient, which may be an antibiotic, antibody, antiviral agent, anticancer agent, analgesic, immunostimulatory agent, hormone, CNS stimulant, antiemetic, anti-histamine, erythropoietin, complement stimulating agent, sedative, muscle relaxant, anesthetic, anticonvulsive, antidepressant, antipsychotic, or combinations thereof.
The claim coverage centers on methods for treating Gram-negative bacterial infections using specifically defined T3SS inhibitor compounds, optionally in combination with other therapeutic agents or antibiotics, thus providing a novel approach to combating infections involving type III secretion systems.
Stated Advantages
The invention provides inhibitors that specifically block T3SS-mediated secretion and translocation of bacterial effectors, thereby targeting a key virulence factor without affecting bacterial growth.
The disclosed compounds allow the host's immune system to effectively clear infections in cases where bacterial virulence has been neutralized by T3SS inhibition.
T3SS inhibitors can be used as adjunctive therapies with antibiotics, offering a new approach to combat infections, particularly those due to drug-resistant bacteria.
The compounds exhibit minimal cytotoxicity toward mammalian cells, with demonstrated CC50 values at or above 100 μM, providing a favorable selectivity index.
The specificity of the compounds for T3SS and lack of effect on type II secretion and bacterial growth minimize disruption of beneficial microbiota and reduce potential for side effects.
Some T3SS inhibitors described have broad spectrum activity and are effective against multiple Gram-negative bacterial genera possessing type III secretion systems.
Documented Applications
Use in treating infections caused by Gram-negative bacteria with type III secretion systems, particularly Pseudomonas aeruginosa, Yersinia pestis, and Chlamydia trachomatis.
Administration as antibacterial or bacteriostatic agents for individuals exposed to or infected by bacteria with type III secretion systems.
Adjunctive therapy in combination with other agents such as antibiotics, antibodies, or immunostimulatory agents to enhance treatment outcomes.
Use in pharmaceutical compositions for a variety of administration routes including intravenous, oral, topical, nasal, and others, for human or animal patients.
Application in supporting or enabling the individual's immune system to clear or kill infecting or contaminating bacteria by inhibiting T3SS.
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