Antimicrobial, Antibiofilm, and Anti-persister Activities of Penfluridol Against Staphylococcus aureus

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.

Cec4-Derived Peptide Inhibits Planktonic and Biofilm-Associated Methicillin Resistant Staphylococcus epidermidis

“…Specifically, cell wall-related genes in bacteria upregulated under C9 treatment, among them, RS05660 and dltD , are involved in the biosynthesis of peptidoglycan in the cell wall ( 40 ) and the esterification of lipoteichoic acid by d -alanine ( 41 ), thereby affecting the biosynthesis of the bacterial cell wall. While vraX is upregulated after exposure to drugs related to cell membrane or cell wall metabolic damage, such as penfluridol ( 42 ) and vancomycin ( 43 ). In addition, RS02830 is a MarR family transcriptional regulator with a homolog protein in S. epidermidis , TcaR, which is involved in staphylococcal resistance to teicoplanin and methicillin ( 44 ); this regulator also acts as a negative transcriptional regulator of the ica locus and is involved in the regulation of proteins related to the biosynthesis of poly-β-1,6- N -acetyl- d -glucosamine (PNAG; negative regulation) ( 45 ).…”

Pixantrone Sensitizes Gram-Negative Pathogens to Rifampin

“…The bacterial suspension was further incubated with either PIX (32 μg/mL) or RFP (1/4 × MIC) alone or in combination at 37°C and 180 rpm for 8 h. Then, the bacterial suspension was stained with SYTO 9 (10 μM) and PI (10 μM) for 15 min at room temperature in the dark. The morphology was imaged by CLSM (Zeiss LSM 800) with excitation/emission wavelengths of 488 nm/550 nm and 540 nm/620 nm for SYTO 9 and PI, respectively, and analyzed by ImageJ software ( 60 ).…”

Insights into the antimicrobial effects of ceritinib against Staphylococcus aureus in vitro and in vivo by cell membrane disruption

“…As described by our previously reported article (Liu et al 2021 ). The ATP release of S. aureus ATCC 43300 was measured by an Enhanced ATP Assay Kit (Beyotime, Shanghai, China).…”

“…To form persisters of S. aureus strains, the culture was prepared at 37 °C with shaking at 200 rpm for 24 h, washed three times with PBS, and adjusted to OD 600 = 0.2. A 1–8 × MIC CERI (10 × MIC VAN and CIP as control) was added, and CFU counting was performed as described above at the time points of 0, 2, 4, 6, and 8 h (Liu et al 2021 ).…”