Abstract
In an effort to find new repurposed antibacterial compounds, we performed the screening of an FDA-approved compounds library against Staphylococcus aureus American Type Culture Collection (ATCC) 25923. Compounds were evaluated for their capacity to prevent both planktonic growth and biofilm formation as well as to disrupt pre-formed biofilms. One of the identified initial hits was fingolimod (FTY720), an immunomodulator approved for the treatment of multiple sclerosis, which was then selected for follow-up studies. Fingolimod displayed a potent activity against S. aureus and S. epidermidis with a minimum inhibitory concentration (MIC) within the range of 12–15 µM at which concentration killing of all the bacteria was confirmed. A time–kill kinetic study revealed that fingolimod started to drastically reduce the viable bacterial count within two hours and we showed that no resistance developed against this compound for up to 20 days. Fingolimod also displayed a high activity against Acinetobacter baumannii (MIC 25 µM) as well as a modest activity against Escherichia coli and Pseudomonas aeruginosa. In addition, fingolimod inhibited quorum sensing in Chromobacterium violaceum and might therefore target this signaling pathway in certain Gram-negative bacteria. In conclusion, we present the identification of fingolimod from a compound library and its evaluation as a potential repurposed antibacterial compound.
Highlights
Infections involving multi-drug resistant bacteria have become extremely harder to treat, as many of the currently used antibiotics are less effective, which has boosted the awareness of the urgent need for new drugs and therapeutic options in recent years [1,2,3]
Fingolimod is an analogue of sphingosine 1-phosphate (S1P) that is currently used in the treatment of relapsing multiple sclerosis
Fingolimod is likely to target metabolically active cells in Gram-positive strains as it starts showing the observable killing of viable cells during the early stages of growth
Summary
Infections involving multi-drug resistant bacteria have become extremely harder to treat, as many of the currently used antibiotics are less effective, which has boosted the awareness of the urgent need for new drugs and therapeutic options in recent years [1,2,3]. Biofilm-related infections represent a majority of all bacterial infections and can affect a large variety of organs [5,10] They are found in up to 60% of chronic wound infections and are prevalent in infections occurring in medical devices, such as orthopedic implants and catheters, as non-biological foreign material offers a ready surface for colonization by single bacteria [11,12,13,14]. Over 50% of all urinary catheters will become infected within two weeks, and up to 2% of all orthopedic alloplastic devices and 4% of heart valves and pacemakers will eventually become infected [15,16] In those cases, as biofilms cannot be fully destroyed by antibiotic treatments, a chronic infection settles and the device needs to be surgically replaced, a procedure that implicates risks and morbidity [16,17]. The prevention of biofilm formation is the method of choice to combat device-related infections
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