Modulating Adenylyl Cyclase for the Treatment of Bacterial or Eukaryotic Infections

During pathogenesis in a host, an infecting organism is challenged to respond to a diverse and dynamic set of environmental conditions. A variety of pathogenic organisms have evolved to exploit the dramatic environmental shifts encountered once inside an infectible host as a signal to alter their growth and virulence properties. One such environmental signal that pathogenic organisms exploit is the change in concentration of CO2, HCO3-, and/or pH: there is a 150-fold difference in CO2 concentration inside the human (or animal) body (5% CO2) compared to the atmosphere (0.03% CO2). Because CO2 levels are in equilibrium with the concentration of bicarbonate and pH levels, the infectious organisms may sense differences in concentration of CO2, HCO3-, or pH levels.

Cyclic-3?۪, 5?۪-adenosine monophosphate (cAMP) mediates cellular responses to nutritional conditions and extracellular conditions in organisms from bacteria to humans. Adenylyl cyclase (AC) is a group of enzymes that catalyze the conversion of ATP to cAMP. Many different studies indicates that CO2 / HCO3-/pH -sensing ACs exist in both prokaryotic (bacterial) and eukaryotic pathogens.

Cornell researchers demonstrated that, in fungal pathogens Candida and Cryptococcus, the ACs are CO2 / HCO3- sensitive, and when they are inhibited by small molecules, the morphological transition essential for pathogenesis is blocked. In parasitic protozoa, the researchers demonstrated that the CO2 / HCO3- regulated AC in malaria-causing Plasodium is essential for growth inside red blood cells. ACs have also genetically been shown to be important for the expression of virulence factors in other infectious protozoa.

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

Potential Applications

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

Advantages

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