Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent

Abstract

The rapid rise of bacterial resistance to traditional antibiotics combined with the decline in discovery of novel antibacterial agents has created a global public health crisis. Repurposing existing drugs presents an alternative strategy to potentially expedite the discovery of new antimicrobial drugs. The present study demonstrates that simvastatin, an antihyperlipidemic drug exhibited broad-spectrum antibacterial activity against important Gram-positive (including methicillin-resistant Staphylococcus aureus (MRSA)) and Gram-negative pathogens (once the barrier imposed by the outer membrane was permeabilized). Proteomics and macromolecular synthesis analyses revealed that simvastatin inhibits multiple biosynthetic pathways and cellular processes in bacteria, including selective interference of bacterial protein synthesis. This property appears to assist in simvastatin’s ability to suppress production of key MRSA toxins (α-hemolysin and Panton-Valentine leucocidin) that impair healing of infected skin wounds. A murine MRSA skin infection experiment confirmed that simvastatin significantly reduces the bacterial burden and inflammatory cytokines in the infected wounds. Additionally, simvastatin exhibits excellent anti-biofilm activity against established staphylococcal biofilms and demonstrates the ability to be combined with topical antimicrobials currently used to treat MRSA skin infections. Collectively the present study lays the foundation for further investigation of repurposing simvastatin as a topical antibacterial agent to treat skin infections.

Is There Potential for Repurposing Statins as Novel Antimicrobials?

“…In contrast, however, Bergman et al, using a maximum concentration of 250 mg/liter, observed that simvastatin did not inhibit the growth of H. influenzae (43), while Graziano et al found that simvastatin, atorvastatin, and pravastatin at concentrations up to 250 mg/liter did not inhibit the growth of P. aeruginosa, E. coli, or Enterococcus faecalis (42). Furthermore, a study by Thangamani et al (41) indicated that, while the growth of Gram- (41,42), it is worth noting that the E. coli ATCC 3218 assays were performed on solid agar while the other studies were performed using the broth microdilution method, perhaps explaining the apparent differences in activity. Taken together, the data suggest that the antibacterial activity of statins may be statin specific and/or strain/species specific or both.…”

“…A number of studies have investigated the impact of statin treatment on in vitro bacterial virulence ( (41,42). The latter study by Thangamani et al also showed that simvastatin treatment suppressed the production of the S. aureus toxins Panton-Valentine leucocidin (PVL) and ␣-hemolysin (Hla) produced by MRSA.…”

“…Wang et al showed that application of simvastatin (62.5 mg/liter) reduced the MSSA wound size by over 50% at day 7 and significantly reduced (Ͼ60% reduction) the bacterial load visible in the wound histology (40), while Thangamani et al showed that topical simvastatin at concentrations of 1% and 3% significantly reduced the bacterial load in MRSA wounds by 75% and 90%, respectively (41). The latter study also showed that this topical application of simvastatin had an additive healing effect and that it reduced the production of proinflammatory cytokines (interleukin-6 [IL-6], tumor necrosis factor alpha [TNF-␣], and IL-1␤) in MRSA-infected wound lesions.…”

“…Taken together, the data suggest that the antibacterial activity of statins may be statin specific and/or strain/species specific or both. Simvastatin and atorvastatin generally appear to be more effective against S. aureus, S. pneumoniae, and enterococci than other statins (37)(38)(39)43), while three distinct simvastatin MICs were reported against S. aureus clinical isolates from the United Kingdom and Jordan as well as against typed reference strains (Table 1) (37,38,41,42). It is also noteworthy that, while the MICs of statins varied according to the statin and pathogen tested, the in vitro MICs ranged from circa 15 to 400 mg/liter, far exceeding the range of typical peak plasma concentrations of patients on oral statins, which generally range from circa 10 to 300 g/liter.…”

“…However, two studies have recently demonstrated the in vivo clinical efficacy of locally high concentrations of statins, whereby topical applications of simvastatin at MIC/sub-MICs significantly enhanced bacterial clearance and healing of methicillin-sensitive S. aureus (MSSA)-and MRSA-contaminated wounds in mouse wound models (40,41). Wang et al showed that application of simvastatin (62.5 mg/liter) reduced the MSSA wound size by over 50% at day 7 and significantly reduced (Ͼ60% reduction) the bacterial load visible in the wound histology (40), while Thangamani et al showed that topical simvastatin at concentrations of 1% and 3% significantly reduced the bacterial load in MRSA wounds by 75% and 90%, respectively (41).…”