|Agency:||Department of Health and Human Services|
|Branch:||National Institutes of Health|
|Agency Tracking Number:||R44GM110848|
|Solicitation Topic Code:||300|
The nontuberculous Mycobacteria NTM are a growing public health concern as the number of opportunistic infections increases. Although not a reportable disease, there is growing epidemiologic evidence to suggest that NTM causes more infections today in the United States than Mycobacterium tuberculosis Mtb. Unlike Mtb, however, there are few dedicated antimicrobial drug discovery programs specifically for NTM Pulmonary disease caused by NTM. This is especially problematic in patients with underlying susceptibilities such as immunosuppressive medications cystic fibrosis and other lung diseases HIV and malignancies. Given the emergence of NTM as a public health issue, finding new antibacterial agents is of high importance. We have screened libraries of novel compounds for anti NTM activity focusing on M abscessus Mab and identifying several promising small molecule screening hits with chemically tractable scaffolds.
Our Phase I SBIR grant focused on initial medicinal chemistry optimization of early drug leads that exhibited minimal cytotoxicity high metabolic stability and low potential for resistance development. We achieved minimum inhibitory concentration MIC values ranging from to g mL for rapidly growing Mycobacteria RGM including Mab M chelonae M fortiutum and M peregrinum. Importantly, these compounds also have activity against Mtb MIC to g mL and against permeabilized Gram negative bacteria GNB potentially enabling us to attain broad spectrum antibacterial activity.
We propose to continue development of a very promising benzothiazole cyclohexylcarboxamide series with Phase II SBIR support focusing on advanced medicinal chemistry lead optimization with a goal of obtaining a strong drug candidate with demonstrated in vivo activity.
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