Transferrin iron starvation therapy for lethal bacterial and fungal infections.
New strategies to treat antibiotic-resistant infections are urgently needed. We serendipitously discovered that stem cell conditioned media possessed broad antimicrobial properties. Biochemical, functional, and genetic assays confirmed that the antimicrobial effect was mediated by supra-physiological concentrations of transferrin. Human transferrin inhibited growth of gram-positive (Staphylococcus aureus), gram-negative (Acinetobacter baumannii), and fungal (Candida albicans) pathogens by sequestering iron and disrupting membrane potential. Serial passage in subtherapeutic transferrin concentrations resulted in no emergence of resistance. Infected mice treated with intravenous human transferrin had improved survival and reduced microbial burden. Finally, adjunctive transferrin reduced the emergence of rifampin-resistant mutants of S. aureus in infected mice treated with rifampin. Transferrin is a promising, novel antimicrobial agent that merits clinical investigation. These results provide proof of principle that bacterial infections can be treated in vivo by attacking host targets (ie, trace metal availability) rather than microbial targets.
The Los Angeles Biomedical Research Institute, Torrance, California The Division of General Internal Medicine, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance The David Geffen School of Medicine at UCLA, Los Angeles.
Lin
L
Lin
The Los Angeles Biomedical Research Institute, Torrance, California.
Paul
P
Pantapalangkoor
The Los Angeles Biomedical Research Institute, Torrance, California.
Brandon
B
Tan
The Los Angeles Biomedical Research Institute, Torrance, California The Division of General Internal Medicine, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance The David Geffen School of Medicine at UCLA, Los Angeles.
Kevin W
KW
Bruhn
The Los Angeles Biomedical Research Institute, Torrance, California.
Tiffany
T
Ho
The Los Angeles Biomedical Research Institute, Torrance, California.
Travis
T
Nielsen
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Eric P
EP
Skaar
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee.
Yaofang
Y
Zhang
The Los Angeles Biomedical Research Institute, Torrance, California.
Ruipeng
R
Bai
The Los Angeles Biomedical Research Institute, Torrance, California.
Amy
A
Wang
The Los Angeles Biomedical Research Institute, Torrance, California.
Terence M
TM
Doherty
The Los Angeles Biomedical Research Institute, Torrance, California The Division of General Internal Medicine, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance The David Geffen School of Medicine at UCLA, Los Angeles.
Brad
B
Spellberg
D000151:Acinetobacter Infections / Q000188:drug therapy*; D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D000818:Animals; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D002177:Candidiasis / Q000188:drug therapy*; D002478:Cells, Cultured; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D014168:Transferrin / Q000008:administration & dosage*; D016896:Treatment Outcome
D014168:Transferrin; D007501:Iron
Acinetobacter baumannii; Candida albicans; Staphylococcus aureus; in vivo treatment; iron; transferrin