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Novel Targets for Anti-Infectives against Eukaryotic Pathogens

詳細技術說明

Thisinvention provides a method and compositions for preventing or treatinginfections caused by bacterial or eukaryotic pathogens by administering modulatorsof adenylyl cyclase of the pathogens.

*Abstract

During pathogenesis in a host, aninfecting organism is challenged to respond to a diverse and dynamic set ofenvironmental conditions.  A variety ofpathogenic organisms have evolved to exploit the dramatic environmental shiftsencountered once inside an infectible host as a signal to alter their growthand virulence properties.  One suchenvironmental signal that pathogenic organisms exploit is the change inconcentration of CO₂, HCO₃^-, and/or pH: thereis a 150-fold difference in CO₂ concentration inside the human (oranimal) body (5% CO₂) compared to the atmosphere (0.03% CO₂). Because CO₂ levels are inequilibrium with the concentration of bicarbonate and pH levels, the infectiousorganisms may sense differences in concentration of CO₂, HCO₃^-,or pH levels.    

 

Cyclic-3’, 5’-adenosinemonophosphate (cAMP) mediates cellular responses to nutritional conditions andextracellular conditions in organisms from bacteria to humans.  Adenylyl cyclase (AC) is a group of enzymesthat catalyze the conversion of ATP to cAMP. Many different studies indicates that CO₂ / HCO₃^-/pH-sensing ACs exist in both prokaryotic (bacterial) and eukaryoticpathogens. 

 

Cornell researchers demonstratedthat, in fungal pathogens Candida andCryptococcus, the ACs are CO₂/ HCO₃^- sensitive, and when they are inhibited by smallmolecules, the morphological transition essential for pathogenesis isblocked.  In parasitic protozoa, theresearchers demonstrated that the CO₂ / HCO₃^-regulated AC in malaria-causing Plasodiumis essential for growth inside red blood cells. ACs have also genetically beenshown to be important for the expression of virulence factors in otherinfectious protozoa.

 

Therefore, targeting the bacterial andeukaryotic adenylnyl cyclase, and particularly the CO₂/ HCO₃^-/pH- sensing adenylyl cyclases, represents a novel opportunity for the preventionand treatment of infection caused by bacterial and eukaryotic pathogens.

 

PotentialApplications

• Therapeutic treatment for diseases caused bacterialpathogens, especially bacterial pathogens resistant to antibiotics
• Therapeutic treatment for diseases caused eukaryoticpathogens

 

Advantages

• Novel therapeutic target which could be effective forbacterial pathogens resistant to antibiotics
• Noveltherapeutic target for many eukaryotic pathogens

*Licensing

Brian J. Kellybjk44@cornell.edu212-746-6186

其他

• Adenylyl cyclases as novel targets for antibactrialinterventions.  Issued US patent 9,017,681.
• Adenylyl cyclases as novel targets for the treatment ofinfection by eukaryotic pathogens. Issued US patent 9,095,578.

國家/地區

美國