title: 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.
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Shankar
authors.initials: S
authors.lastname: Thangamani
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Haroon
authors.initials: H
authors.lastname: Mohammad
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.|Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
authors.forename: Mostafa F N
authors.initials: MF
authors.lastname: Abushahba
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.|Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt.
authors.forename: Maha I
authors.initials: MI
authors.lastname: Hamed
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Tiago J P
authors.initials: TJ
authors.lastname: Sobreira
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Victoria E
authors.initials: VE
authors.lastname: Hedrick
authors.affiliation: Bindley Bioscience Center, Purdue University, West Lafayette, IN, USA.
authors.forename: Lake N
authors.initials: LN
authors.lastname: Paul
authors.affiliation: Department of Comparative Pathobiology, Purdue University College of Veterinary Medicine, West Lafayette, IN, USA.
authors.forename: Mohamed N
authors.initials: MN
authors.lastname: Seleem
mesh_terms: D000287:Administration, Topical; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004357:Drug Synergism; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000378:metabolism; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D018836:Inflammation Mediators / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008826:Microbial Sensitivity Tests; D059748:Proteolysis; D019821:Simvastatin / Q000494:pharmacology*; D013207:Staphylococcal Skin Infections / Q000188:drug therapy / Q000378:metabolism / Q000382:microbiology; D013210:Staphylococcus / Q000187:drug effects / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D016207:Cytokines; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000960:Hypolipidemic Agents; D018836:Inflammation Mediators; D019821:Simvastatin