A potent synthetic inorganic antibiotic with activity against drug-resistant pathogens.
The acronymously named "ESKAPE" pathogens represent a group of bacteria that continue to pose a serious threat to human health, not only due to their propensity for repeated emergence, but also due to their ability to "eskape" antibiotic treatment. The evolution of multi-drug resistance in these pathogens alone has greatly outpaced the development of new therapeutics, necessitating an alternative strategy for antibiotic development that considers the evolutionary mechanisms driving antibiotic resistance. In this study, we synthesize a novel inorganic antibiotic, phosphopyricin, which has antibiotic activity against the Gram-positive methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). We show that this potent antibiotic is bactericidal, and exhibits low toxicity in an acute dose assay in mice. As a synthetic compound that does not occur naturally, phosphopyricin would be evolutionarily foreign to microbes, thereby slowing the evolution of resistance. In addition, it loses antibiotic activity upon exposure to light, meaning that the active antibiotic will not accumulate in the general environment where strong selective pressures imposed by antibiotic residuals are known to accelerate resistance. Phosphopyricin represents an innovation in antimicrobials, having a synthetic core, and a photosensitive chemical architecture that would reduce accumulation in the environment.
Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan, S4S0A2, Canada.
Shelby
S
Hubick
Department of Chemistry and Biochemistry, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan, S4S0A2, Canada.
Arumugam
A
Jayaraman
Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan, S4S0A2, Canada.
Alexander
A
McKeen
College of Pharmacy and Nutrition, University of Saskatchewan, 104 Clinic Place, Saskatoon, Saskatchewan, S7N2Z4, Canada.
Shelby
S
Reid
College of Pharmacy and Nutrition, University of Saskatchewan, 104 Clinic Place, Saskatoon, Saskatchewan, S7N2Z4, Canada.
Jane
J
Alcorn
Department of Biology, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan, S4S0A2, Canada.
John
J
Stavrinides
Department of Chemistry and Biochemistry, University of Regina, 3737 Wascana Parkway, Regina, Saskatchewan, S4S0A2, Canada.
Brian T
BT
Sterenberg
D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000302:isolation & purification; D001424:Bacterial Infections / Q000188:drug therapy* / Q000382:microbiology; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects*; D005260:Female; D007287:Inorganic Chemicals / Q000737:chemistry*; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D009942:Organometallic Compounds / Q000737:chemistry* / Q000494:pharmacology*
D000900:Anti-Bacterial Agents; D007287:Inorganic Chemicals; D009942:Organometallic Compounds; C000629071:phosphopyricin