Abstract
Staphylococcus aureus has increasingly attracted global attention as a major opportunistic human pathogen owing to the emergence of biofilms (BFs) and persisters that are known to increase its antibiotic resistance. However, there are still no effective antimicrobial agents in clinical settings. This study investigated the antimicrobial activity of penfluridol (PF), a long-acting antipsychotic drug, against S. aureus and its clinical isolates via drug repurposing. PF exhibited strong bactericidal activity against S. aureus, with a minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of 4–8 and 16–32 μg/ml, respectively. PF could significantly inhibit biofilm formation and eradicate 24 h preformed biofilms of S. aureus in a dose-dependent manner. Furthermore, PF could effectively kill methicillin-resistant S. aureus (MRSA) persister cells and demonstrated considerable efficacy in a mouse model of subcutaneous abscess, skin wound infection, and acute peritonitis caused by MRSA. Notably, PF exerted almost no hemolysis activity on human erythrocytes, with limited cytotoxicity and low tendency to cause resistance. Additionally, PF induced bacterial membrane permeability and ATP release and further caused membrane disruption, which may be the underlying antibacterial mechanism of PF. In summary, our findings suggest that PF has the potential to serve as a novel antimicrobial agent against S. aureus biofilm- or persister-related infections.
Highlights
Staphylococcus aureus is an important opportunistic human pathogen that often causes disease in community and hospital settings (van Dalen et al, 2020)
The number of regenerated persister cells after 24 h of antibiotics treatment was slightly more than the initial bacterial count (Biofilm + RFP 24 h), and the germicidal efficacy of persisters treated with 8× minimum inhibitory concentration (MIC) PF was still the most significant (Figure 3C). These results suggested that PF effectively killed methicillin-resistant S. aureus (MRSA) planktonic and biofilm persister cells in a dose-dependent and time-dependent manner
We found that the antipsychotics drug PF exhibited strong antimicrobial effects against S. aureus
Summary
Staphylococcus aureus is an important opportunistic human pathogen that often causes disease in community and hospital settings (van Dalen et al, 2020). Staphylococcus aureus is both a frequent commensal and a leading cause of nosocomial infections, including bacteremia, osteomyelitis, endocarditis, and skin and soft tissue infections (Turner et al, 2019). It is urgent to develop new antimicrobial drugs to combat biofilm-associated infection, as it is proving difficult for traditional antibiotics to effectively eradicate the biofilms formed in the body (Koo et al, 2017)
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