Abstract
MreB is a cytoskeleton protein present in rod-shaped bacteria that is both essential for bacterial cell division and highly conserved. Because most Gram (-) bacteria require MreB for cell division, chromosome segregation, cell wall morphogenesis, and cell polarity, it is an attractive target for antibacterial drug discovery. As MreB modulation is not associated with the activity of antibiotics in clinical use, acquired resistance to MreB inhibitors is also unlikely. Compounds, such as A22 and CBR-4830, are known to disrupt MreB function by inhibition of ATPase activity. However, the toxicity of these compounds has hindered efforts to assess the in vivo efficacy of these MreB inhibitors. The present study further examines the structure-activity of analogs related to CBR-4830 as it relates to relative antibiotic activity and improved drug properties. These data reveal that certain analogs have enhanced antibiotic activity. In addition, we evaluated several representative analogs (9, 10, 14, 26, and 31) for their abilities to target purified E. coli MreB (EcMreB) and inhibit its ATPase activity. Except for 14, all these analogs were more potent than CBR-4830 as inhibitors of the ATPase activity of EcMreB with corresponding IC50 values ranging from 6 ± 2 to 29 ± 9 µM.
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This research was supported in part by a Research Agreement between EJLV at Rutgers University and TAXIS Pharmaceuticals, Inc. as well as National Institutes of Health grant RO1 AI118874 to DSP.
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The authors declare the following competing financial interest(s): EJLV and DSP are co-founders of TAXIS Pharmaceuticals, Inc. and AKPP is a shareholder and therefore have a financial interest in the company.
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Sagong, H.Y., Rosado-Lugo, J.D., Bryan, E.J. et al. Novel MreB inhibitors with antibacterial activity against Gram (-) bacteria. Med Chem Res 31, 1679–1704 (2022). https://doi.org/10.1007/s00044-022-02967-y
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DOI: https://doi.org/10.1007/s00044-022-02967-y