Abstract
<jats:p>Background: Antimicrobial resistance is at alarming levels. Methicillin resistant Staphylococcus aureus is a major cause of clinical concern and has been classified as part of the so called ESKAPE pathogens. The increase in resistance coupled with the lack of new agents in development has demanded innovative ways of developing new antimicrobials. Methods. Here we investigate an approved drug (Zafirlukast) which has previously reported to have activity against mycobacterium for activities against other bacterial strains. Antibacterial activity was assessed using standard MIC testing along with checkerboard analysis to investigate potential synergies/antagonisms. In order to define any MOA a number of zafirlukast resistant mutant strains of MRSA (generated via serial passage) were sequenced. Biochemical analysis was performed on the target pathway to confirm the putative target of Zafirlukast in Staphylococcus aureus. Results: It was found that Zafirlukast possessed modest direct acting antimicrobial activity (0.5-32 mg/mL) against a panel of Gram-positive bacteria including importantly MRSA. It was also found that Zafirlukast synergised with a number of existing antibiotics. Remarkably mutants which were forced to be resistant to Zafirlukast become resensitised to the b-lactams that they were originally resistant to. This is potentially a very useful property of a pontiator drug. Mutational analysis suggested the target of Zafirlukast in Staphylococci is LtaS (Lipoteichoic acid synthase) of which there are no current approved inhibitors. Teichoic acid pathway involvement was confirmed via biochemical analysis. Conclusion: Here we establish that zafirlukast has activities beyond mycobacterium and gingivalis, encompassing many Gram positives including MRSA and for the first time report its putative target as LtaS. The repurposing of safe to use drugs is an attractive strategy to derisk drug discovery programs. Zafirlukast has many attractive antimicrobial activities which may encourage further investigations in this field. However, it should be noted that whilst it may represent a safe starting scaffold further chemistry is likely to be needed for it to be used in the antimonial setting.</jats:p>