Advantages
- Novel Mechanism of Action: These small-molecule compounds increase S403-phosphorylated p62, promoting the construction of autophagosome. This mechanism activates selective autophagy system, leading bacterial degradation.
- Efficacy Against Intracellular Bacteria: With their novel mechanism of action, these compounds are expected to exhibit effective antimicrobial activity against intracellular bacteria, which are resistant to existing antimicrobial agents.
Technology Overview & Background
Non-tuberculous mycobacteria (NTM) pulmonary disease is a respiratory infection caused by NTM, a group of bacteria whose incidence has been rising rapidly in recent years. According to a 2014 survey conducted in Japan, the disease’s incidence was reported as 14.7 cases per 100,000 person-years—higher than that of pulmonary tuberculosis.
NTM is a generic term referring to mycobacteria other than Mycobacterium tuberculosis and Mycobacterium leprae. Over 250 species of NTM have been identified, with the Mycobacterium avium complex (MAC)—a combination of M. avium and M. intracellulare—being the most common causative agent, responsible for approximately 90% of cases.
Current treatment challenges include widespread resistance to conventional antimicrobial agents and the bacteria’s intracellular parasitic nature, which increases the risk of recurrence and necessitates prolonged drug administration. Therefore, the development of new therapeutic agents is urgently needed.
Researchers have discovered that phosphorylation of the 403rd serine residue of p62, a key adaptor protein in selective autophagy, significantly enhancesthe construction of autophagosome. This facilitates the incorporation of ubiquitinated proteins. Leveraging this insight, the researchers developed a cell-based screening system to identify small-molecule compounds that increase S403-phosphorylated p62.
The newly developed compounds (ADI compounds) have demonstrated promising effects, including the inhibition of phosphorylated tau aggregate degradation in the brain and hippocampal atrophy in a mouse model of tauopathy (PS19). These compounds are considered promising candidates for therapeutic drugs aimed at inducing autophagy to degrade intracellular bacteria.
Data Highlights
In Vitro Studies:
- Treatment of macrophage cells infected with M. avium using ADI compounds resulted in a significant reduction in the number of viable intracellular bacteria.
- A concentration-dependent decrease in viable intracellular bacteria was observed when macrophages infected with clarithromycin (CAM)-resistant M. avium were treated with a combination of CAM and ADI compounds.
In Vivo Studies:
Currently ongoing.
Patent
- Patent pending (not yet published).
Principal Investigators & Academic Institution
Assistant Professor Satoshi Mizuta (Nagasaki University Graduate School of Biomedical Sciences).
Associate Professor Gen Matsumoto (Osaka Metropolitan University Graduate School of Medicine).
Expectations
TECH MANAGE CORP. is looking for a pharmaceutical company/start-up that is interested in developing antibacterial drugs based on this research project. Discussions regarding the evaluation of the compounds are also welcome. If interested, we would be delighted to arrange a meeting with our researchers to explore potential licensing/collaboration opportunities.
Project No.TT-05171