Inhibitors of bacterial type III secretion system
Inventors
Moir, Donald T. • Aiello, Daniel • Peet, Norton P. • Williams, John D. • Torhan, Matthew
Assignees
Publication Number
US-9340551-B2
Publication Date
2016-05-17
Expiration Date
2032-07-13
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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, Psendomonas spp., Yersinia spp., en tero pathogenic and enteroinvasive Escherichia coli, and Chlamydia spp. having such type III secretion systems.
Core Innovation
The invention provides a family of organic compounds that function as inhibitors of the bacterial type III secretion system (T3SS), which is responsible for the secretion and translocation of effector toxins from Gram-negative bacteria directly into host cells. These compounds, particularly based on a phenoxyacetamide scaffold with specific structural modifications, are developed to inhibit T3SS-mediated secretion and translocation of bacterial effectors, especially from pathogens such as Pseudomonas aeruginosa, Yersinia pestis, and Chlamydia trachomatis.
The underlying problem targeted by this invention is the critical role that T3SS plays in the virulence of various Gram-negative bacterial pathogens. T3SS contributes to the progression and severity of infections by enabling bacteria to evade or suppress the host immune response. The significance is heightened by increases in drug-resistant strains, and conventional antibiotics are often insufficient to manage persistent or acute infections, especially those caused by P. aeruginosa. Hence, new therapeutic agents targeting bacterial virulence factors are needed.
The compounds described in the invention are shown to possess higher potency and lower cytotoxicity than previously reported T3SS inhibitors, with effectiveness in inhibiting both T3SS-mediated secretion and translocation in relevant bacterial species. The structural optimization, such as introducing an ethyl substituent at the α carbon, confers a significant increase in inhibitory activity and improves selectivity. Both racemic mixtures and the isolated R-isomer are considered preferred embodiments, with experimental results confirming that inhibitory properties reside primarily in the R-isomer.
Claims Coverage
The patent contains several independent claims outlining three main inventive features.
Bacterial type III secretion system inhibitor compound of formula I
A compound defined by a general formula (formula I) comprising: - A core scaffold where A is independently CH or N. - X is independently hydrogen or halogen. - Z can be O, S, NH, or NR3 (R3 is alkyl). - R1, R1′, R1″ are independently hydrogen, halogen, alkyl, hydroxy, alkoxy, alkylthio, or cyano (no more than two hydrogens). - V is NR2, O, or CR3R4 (R2, R3, R4 are hydrogen or alkyl). - Y is a divalent alkyl/alkenyl/alkynyl radical with 1 to 6 carbon atoms, optionally containing heteroatoms and up to four specific substituents, or oxygen, or NR5 (R5 is hydrogen or alkyl). - W is an aryl or heteroaryl radical forming a 5- or 6-membered ring, optionally fused with further rings and optionally further substituted. The formula covers variants as racemic mixtures and as isolated R-isomers, considering the asymmetric carbon.
Bacterial type III secretion system inhibitor compound of formula III
A compound of formula III wherein: - A is CH or N. - X is hydrogen or halogen. - R is hydrogen or methyl. - Y is a divalent straight-chain, branched, or cyclic alkyl, alkenyl, or alkynyl radical (1–6 carbons), optionally containing heteroatoms and substituents as specified. - Z is O, S, NH, or NR3. - W is an aryl or heteroaryl radical forming a 5- or 6-membered ring, optionally with further ring fusion and specific substituents. The claim further specifies that at least one X is Cl and the other X is hydrogen, F, or Cl; Y is —CH2—, —CH(CH3)—, or —C(CH3)2—; and W is further defined by the claim.
Pharmaceutical composition comprising one or more bacterial T3SS inhibitor compounds and a pharmaceutically acceptable carrier or excipient
A pharmaceutical composition comprising: - One or more T3SS inhibitor compounds as disclosed in claim 1. - A pharmaceutically acceptable carrier or excipient. Such compositions may utilize the R-isomer in substantially pure form.
Method for treating an individual infected with or exposed to a Gram-negative bacterium
A method comprising: - Administering to an individual an effective amount to inhibit T3SS-mediated effector secretion of a compound according to claim 1. - The individual can be human. - The Gram-negative bacterium is of the genus Pseudomonas, Salmonella, Yersinia, or Chlamydia, including specifically Pseudomonas aeruginosa, Yersinia pestis, or Chlamydia trachomatis. - The method may further include administering an additional active ingredient selected from antibiotics, antibodies, antiviral agents, anticancer agents, analgesics, immunostimulatory agents, hormones, central nervous system stimulants, antiemetics, anti-histamines, erythropoietin, complement stimulating agents, sedatives, muscle relaxants, anesthetics, anticonvulsives, antidepressants, antipsychotic agents, and combinations thereof.
The claim coverage centers on structurally defined T3SS inhibitor compounds (formulas I and III), pharmaceutical compositions containing them, and methods of treating individuals against infections with Gram-negative bacteria by inhibiting type III secretion systems.
Stated Advantages
The compounds show higher potency (3–4 fold increases) and lower cytotoxicity (>3-fold decrease) compared to previously reported T3SS inhibitor compounds.
The inhibitors are effective against current drug-resistant strains of P. aeruginosa and other Gram-negative pathogens.
The therapeutic approach is species-specific, sparing normal flora and potentially reducing infections associated with local immunosuppression.
These inhibitors are equally potent against multiple P. aeruginosa strains, including clinical isolates, and are not affected by P. aeruginosa efflux mechanisms.
The compounds are not expected to exert significant selection pressure for resistance outside the body and only relatively weak selection pressure during therapy.
When used with an antibacterial agent, these inhibitors may permit the use of lower doses of co-administered antibiotics.
The inhibitors function through a novel antivirulence mechanism, helping to maintain the host's innate immune function rather than directly killing bacteria.
Documented Applications
Use as antivirulence agents to treat bacterial infections, especially those caused by Pseudomonas, Yersinia, or Chlamydia species.
Treatment of infections by Pseudomonas aeruginosa, Yersinia pestis, or Chlamydia trachomatis.
Adjunctive therapy in combination with other antibacterial agents (antibiotics, antibodies, immunostimulatory agents) to provide enhanced treatment of infections.
Formulation into pharmaceutical compositions for administration via intravenous, intramuscular, oral, topical, transdermal, nasal, pulmonary, intrauterine, vaginal, rectal, or other routes for combating bacterial infection.
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