Species-specific inhibitors of methionine adenosyltransferase (MAT)

Project ID: TECH2023-31

Background

Drug resistance, especially to antibiotics and other antimicrobials, is a huge and growing problem. Some bacteria already have untreatable strains, and other microbes have never had good drug options. Broad-spectrum antibiotics have substantial side effects, including microbiome disruption. Cryptosporidium parvum is an opportunistic pathogen of humans and livestock with limited treatment options and no available vaccine. Infection with C. parvum typically results in self-limiting diarrhea and can lead to life-threatening disease for immunocompromised or very young patients. The Cryptosporidium (also known as “Crypto”) parasite has a protective outer layer, which means, chlorinating water may not kill the parasite. Crypto is one of the most common causes of waterborne disease in the United States, and is spread through fecal-oral contact. People with weakened immune systems (e.g., people with HIV/AIDS, those with inherited diseases which affect the immune system, and cancer or transplant patients who are taking certain immunosuppressive drugs) may develop serious, chronic, and sometimes fatal illness from Crypto. There is currently only one FDA-approved drug for cryptosporidiosis, which is nitazoxanide. However, nitazoxanide lacks efficacy in high-risk populations, such as patients living with HIV, and there is limited data on patients with other types of immunosuppression. For infections caused by Pseudomonas aeruginosa, as another example, there are more alternative treatment options, but new agents are needed for this infamously drug-resistant organism. MAT (Methioinine adenosyltrasferase) is a universally-essential enzyme. To date, no species-specific and potent MAT inhibitors of infectious agents have entered clinical use, in part as MAT is so highly conserved.lk Thus today there is still a need in the art for species-specific and potent MAT inhibitors.

Invention Description

A researcher at the University of Toledo has developed potent and species-specific MAT Inhibitors

Applications

• Treatment of drug resistant microorganisms

Advantages

• Targets a high-priority but seriously under-drugged essential enzyme (MAT)
• Shows a degree of species (ortholog) specificity
• Possible treatment for difficult-to-treat and/or highly-resistant organisms
  • Cryptosporidum parvum hits
  • Pseudomonas aeruginosa hits
• Possible activity against three particularly problematic bacteria, based on target pocket sequence identity to Ps. aeruginosa MAT ortholog:
  • Acinetobacter baumanii
  • Enterobacter cloacae
  • Klebsiella pneumoniae