Sorafenib analogues exhibit dual Colistin-potentiating and anti-MRSA activity

In response to the antimicrobial resistance (AMR) global health crisis, physicians have been forced to employ antibiotics of last resort such as colistin, which had previously been removed from clinics due to toxicity concerns. The increase in colistin usage has in turn resulted in the increased incidence of colistin-resistant isolates, making novel therapeutic options for infections caused by these pathogens a priority. We previously reported that sorafenib, a eukaryotic kinase inhibitor, is a colistin adjuvant, augmenting colistin activity against colistin-resistant Klebsiella pneumoniae and Acinetobacter baumannii. Herein, we describe the generation of a library of analogues based upon the sorafenib scaffold, lead compounds from which sensitize colistin-resistant K. pneumoniae, A. baumannii, and Pseudomonas aeruginosa to colistin, and exhibit reduced cytotoxicity compared to sorafenib. We also describe the standalone antimicrobial activity of these sorafenib analogues against methicillin-resistant Staphylococcus aureus (MRSA). Lead compound NDM-773 lowers the colistin minimum inhibitory concentration (MIC) against K. pneumoniae B9 from 512 μg mL^-1 to 2 μg mL^-1 at 1.5 μM, against A. baumannii 4106 from 1024 μg mL^-1 to 1 μg mL^-1 at 4 μM, and against P. aeruginosa TRPA162 from 8192 μg mL^-1 to ≤0.125 μg mL^-1 at 7.5 μM. NDM-773 acts as a standalone antibiotic against MRSA with an MIC of 0.781 μM (0.398 μg mL^-1) and a frequency of mutation rate of <10^-11 against MRSA BAA-1556. NDM-773 exhibits over three-fold reduction in HepG2 toxicity compared to sorafenib, and has therapeutic indices (TIs) up to 35.6 as a colistin adjuvant, and 68.4 as an MRSA antibiotic.