2525. Identification of lead compounds, belonging to 26-membered thiopeptide antibiotics for new anti-tuberculosis therapeutic agents

BACKGROUND: Tuberculosis (TB) is caused by a bacterium called Mycobacterium tuberculosis (Mtb). The incidence of TB patients is increasing globally and the wide spread of multi- and extensively drug-resistant TB poses a significant burden to patients. This situation calls for an urgent medical need to develop new anti-TB drugs. Through our proprietary medicinal chemistry platform on D-series 26-membered thiopeptide, we have identified a few lead compounds, such as AJ-099 and AJ-206 that exert potent activity against multi-drug resistant TB strains. METHODS: In vitro minimal inhibitory concentration (MIC) was measured and a Mtb-infected human macrophage model was used to evaluate anti-mycobacterial activity of our compounds in drug-sensitive or multidrug-resistant TB isolates. Cellular toxicity and some in vitro ADME tests were also performed and examined. RESULTS: We found that our lead compounds exert potent anti-TB activity on H37Rv(MIC: 0.125-0.5 μg/mL) and showed similar MIC levels in multidrug-resistant clinical isolates. In the macrophage infection model, AJ-099 and AJ-206 showed comparable antimycobacterial effects to isoniazid. These compounds showed no cytotoxicity, relatively safe ADME properties, and no hERG inhibition. In vitro antibacterial activity in multi-drug resistant M. tuberculosis strains [Figure: see text] Antibacterial activity in macrophage infection model [Figure: see text] In vitro ADMET properties of lead compounds [Figure: see text] CONCLUSION: AJ-099 and AJ-206 may be potential anti-TB therapeutic agents that possess novel modes of action, low cardiac and cellular toxicities. DISCLOSURES: Young-Jin Son, A&J Science: Employee of A&J Science|A&J Science: Ownership Interest|KHIDI: Grant/Research Support Hee-Jong Hwang, PhD, A&J Science: Stocks/Bonds|KHIDI: Grant/Research Support Clovis Shyaka, n/a, A&J Science: Employee of A&J Science Dahyun Kim, n/a, A&J Science: Employee of A&J Science Jusuk Lee, Ph.D., A&J Science: Employee of A&J Science