UCLA researchers in Department of Molecular and Medical Pharmacology, in collaboration with Hannover Medical School in Germany, have developed a host-directed therapeutic agent targeting mammalian deoxycytidine kinase to prevent, treat, and even cure any local and systemic infectious diseases in human and animal hosts.
BACKGROUND: Many clinically relevant bacterial pathogens have already developed resistance mechanisms against the most common and even last-resort drugs employed today. Hospital- and community-acquired infections caused by antibiotic-resistant bacterial pathogens represent a global public health threat. According to the 2019 antibiotic resistance threat report by the Center for Disease Control and Prevention (CDC), more than 2.8 million antibiotic-resistant infections occur in the United States each year, and more than 35,000 people die as a result. This emergency is being amplified by the rapid exchange of antibiotic resistance genes via horizontal gene transfer events along with the large-scale usage of antimicrobials in hospitals and in livestock industry.
Staphylococcus aureus, or S. aureus, a Gram-positive bacterium, is a notorious pathogen that colonizes approximately 30% of the human population. It causes skin and soft tissue infections and is a very common cause of endocarditis, septic arthritis, osteomyelitis, and bacteremia. In human immune systems, neutrophils combat S. aureus by inducing phagocytosis, producing reactive oxygen species, and making neutrophil extracellular traps (NETs). S. aureus rapidly evades NETs by secreting a potent nuclease, Nuc, capable of disrupting these structures. The Nuc-mediated degradation of NETs, apart from promoting immune evasion, leads to the release of deoxyribonucleoside monophosphates which are then converted into deoxyribonucleosides, such as deoxyadenosine (dAdo) and deoxyguanosine (dGuo). These deoxyribonucleosides disrupt the purine salvage pathway and trigger apoptosis of the host immune cells. Thus, novel methods inhibiting deoxyribonucleoside-mediated cell death could provide new tools for tackling and treating infections by S. aureus and other bacteria.
INNOVATION: UCLA researchers led by Dr. Caius Radu in the Department of Molecular and Medical Pharmacology have developed a novel host-directed therapeutic agent to treat local and/or systemic S. aureus infection in human or animal hosts. The researchers synthesized a family of compounds that evidenced oral activity and potent inhibition of mammalian deoxycytidine kinase (DCK), an enzyme involved in the early steps of the nucleotide salvage pathway in immune cells. They saw that this inhibition is effective at boosting macrophage survival during acute and persistent infections. In in vitro human cell lines and in vivo murine models, the researchers demonstrated that administration of the DCK inhibitor successfully rescued dAdo/dGuo-mediated macrophage cell death and cleared abscess formation by the bacteria. This DCK inhibitor and its derivatives could provide a much-needed therapeutic tool to combat drug-resistant bacterial infections.
POTENTIAL APPLICATIONS:
- This therapeutic method could prevent, attenuate, treat, or cure any local and/or systemic infectious diseases in human or animal hosts, preferably but not limited to an infection caused by S. aureus and its methicillin-resistant or vancomycin-resistant variants.
- These molecules can be used in combination with other therapeutic method to treat against another infectious pathogen, such as Staphylococcus pseudintermedius, or polymicrobial infections
ADVANTAGES:
- The host-directed compound is FDA-approved and safe in humans
- Oral administration allows for easy use in clinical settings
- Broad spectrum activity against multi-resistant bacterial pathogens
DEVELOPMENT-TO-DATE: The therapeutic efficacy of the compounds were successfully demonstrated in human cell line and mouse disease models.
PATENT: US9981961B2
Related Papers (from the inventors only)
Abt, E. R., Rashid, K., Le, T. M., Lee, H. R., Creech, A. L., Wu, T. T., ... & Radu, C. G. (2022). Purine nucleoside phosphorylase regulates metabolic and immune checkpoints. Cancer Research, 82(12_Supplement), 3034-3034.
Abt, E. R., Rosser, E. W., Durst, M. A., Lok, V., Poddar, S., Le, T. M., ... & Radu, C. G. (2020). Metabolic modifier screen reveals secondary targets of protein kinase inhibitors within nucleotide metabolism. Cell chemical biology, 27(2), 197-205.