title: Divergent Isoprenoid Biosynthesis Pathways inStaphylococcusSpecies Constitute a Drug Target for Treating Infections in Companion Animals.
abstract: Staphylococcusspecies are a leading cause of skin and soft tissue infections in humans and animals, and the antibiotics used to treat these infections are often the same. Methicillin- and multidrug-resistant staphylococcal infections are becoming more common in human and veterinary medicine. From a "One Health" perspective, this overlap in antibiotic use and resistance raises concerns over the potential spread of antibiotic resistance genes. Whole-genome sequencing and comparative genomics analysis revealed thatStaphylococcusspecies use divergent pathways to synthesize isoprenoids. Species frequently associated with skin and soft tissue infections in companion animals, includingS. schleiferiandS. pseudintermedius, use the nonmevalonate pathway. In contrast,S. aureus,S. epidermidis, andS. lugdunensisuse the mevalonate pathway. The antibiotic fosmidomycin, an inhibitor of the nonmevalonate pathway, was effective in killing canine clinical staphylococcal isolates but had no effect on the growth or survival ofS. aureusandS. epidermidis. These data identify an essential metabolic pathway inStaphylococcusthat differs among members of this genus and suggest that drugs such as fosmidomycin, which targets enzymes in the nonmevalonate pathway, may be an effective treatment for certain staphylococcal infections.IMPORTANCEDrug-resistantStaphylococcusspecies are a major concern in human and veterinary medicine. There is a need for new antibiotics that exhibit a selective effect in treating infections in companion and livestock animals and that would not be used to treat human bacterial infections. We have identified fosmidomycin as an antibiotic that selectively targets certainStaphylococcusspecies that are often encountered in skin infections in cats and dogs. These findings expand our understanding ofStaphylococcusevolution and may have direct implications for treating staphylococcal infections in veterinary medicine.
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Ana M
authors.identifier: 0000-0002-4645-3895
authors.initials: AM
authors.lastname: Misic
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Christine L
authors.initials: CL
authors.lastname: Cain
authors.affiliation: Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Daniel O
authors.initials: DO
authors.lastname: Morris
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Shelley C
authors.initials: SC
authors.lastname: Rankin
authors.affiliation: Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Beiting
keywords: One Health; Staphylococcus; companion animals; comparative genomics; fosmidomycin; isoprenoid biosynthesis