Potent, specific MEPicides for treatment of zoonotic staphylococci


Autoři: Rachel L. Edwards aff001;  Isabel Heueck aff001;  Soon Goo Lee aff002;  Ishaan T. Shah aff001;  Justin J. Miller aff001;  Andrew J. Jezewski aff003;  Marwa O. Mikati aff001;  Xu Wang aff004;  Robert C. Brothers aff004;  Kenneth M. Heidel aff004;  Damon M. Osbourn aff005;  Carey-Ann D. Burnham aff001;  Sophie Alvarez aff007;  Stephanie A. Fritz aff001;  Cynthia S. Dowd aff004;  Joseph M. Jez aff008;  Audrey R. Odom John aff001
Působiště autorů: Department of Pediatrics, Washington University School of Medicine, St. Louis, Missouri, United States of America aff001;  University of North Carolina-Wilmington, Wilmington, North Carolina, United States of America aff002;  Department of Molecular Microbiology, Washington University School of Medicine, St. Louis, Missouri, United States of America aff003;  Department of Chemistry, George Washington University, Washington, DC, United States of America aff004;  Department of Chemistry, Saint Louis University, St. Louis, Missouri, United States of America aff005;  Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, United States of America aff006;  Department of Agronomy and Horticulture, University of Nebraska-Lincoln, Lincoln, Nebraska, United States of America aff007;  Department of Biology, Washington University, St. Louis, Missouri, United States of America aff008
Vyšlo v časopise: Potent, specific MEPicides for treatment of zoonotic staphylococci. PLoS Pathog 16(6): e32767. doi:10.1371/journal.ppat.1007806
Kategorie: Research Article
doi: 10.1371/journal.ppat.1007806

Souhrn

Coagulase-positive staphylococci, which frequently colonize the mucosal surfaces of animals, also cause a spectrum of opportunistic infections including skin and soft tissue infections, urinary tract infections, pneumonia, and bacteremia. However, recent advances in bacterial identification have revealed that these common veterinary pathogens are in fact zoonoses that cause serious infections in human patients. The global spread of multidrug-resistant zoonotic staphylococci, in particular the emergence of methicillin-resistant organisms, is now a serious threat to both animal and human welfare. Accordingly, new therapeutic targets that can be exploited to combat staphylococcal infections are urgently needed. Enzymes of the methylerythritol phosphate pathway (MEP) of isoprenoid biosynthesis represent potential targets for treating zoonotic staphylococci. Here we demonstrate that fosmidomycin (FSM) inhibits the first step of the isoprenoid biosynthetic pathway catalyzed by deoxyxylulose phosphate reductoisomerase (DXR) in staphylococci. In addition, we have both enzymatically and structurally determined the mechanism by which FSM elicits its effect. Using a forward genetic screen, the glycerol-3-phosphate transporter GlpT that facilitates FSM uptake was identified in two zoonotic staphylococci, Staphylococcus schleiferi and Staphylococcus pseudintermedius. A series of lipophilic ester prodrugs (termed MEPicides) structurally related to FSM were synthesized, and data indicate that the presence of the prodrug moiety not only substantially increased potency of the inhibitors against staphylococci but also bypassed the need for GlpT-mediated cellular transport. Collectively, our data indicate that the prodrug MEPicides selectively and robustly inhibit DXR in zoonotic staphylococci, and further, that DXR represents a promising, druggable target for future development.

Klíčová slova:

Antimicrobial resistance – Esters – Isoprenoids – Staphylococcal infection – Staphylococcus – Zoonoses – Pro-drugs – Phosphonic acids


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