Fe(III)-mediated cellular toxicity.
Because it can undergo reversible changes in oxidation state, iron is an excellent biocatalyst but also a potentially deleterious metal. Iron-mediated toxicity has been ascribed to Fe(II), which reacts with oxygen to generate free radicals that damage macromolecules and cause cell death. However, we now report that Fe(III) exhibits microbicidal activity towards strains of Salmonella enterica, Escherichia coli and Klebsiella pneumoniae defective in the Fe(III)-responding PmrA/PmrB signal transduction system. Fe(III) bound to a pmrA Salmonella mutant more effectively than to the isogenic wild-type strain and exerted its microbicidal activity even under anaerobic conditions. Moreover, Fe(III) permeabilized the outer membrane of the pmrA mutant, rendering it susceptible to vancomycin, which is normally non-toxic to Gram-negative species. On the other hand, Fe(III) did not affect the viability of a mutant defective in Fur, the major regulator of cytosolic iron homeostasis, which is hypersensitive to Fe(II)-mediated toxicity. A functional pmrA gene was necessary for bacterial survival in soil. Our results indicate that Fe(III) exerts its microbicidal activity by a mechanism that is oxygen independent and different from that mediated by Fe(II).
Department of Molecular Microbiology, Howard Hughes Medical Institute, Washington University School of Medicine, St Louis, MO 63110, USA.
Sangpen
S
Chamnongpol
Walter
W
Dodson
Michael J
MJ
Cromie
Z Leah
ZL
Harris
Eduardo A
EA
Groisman
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism; D005290:Ferric Compounds / Q000494:pharmacology*; D005296:Ferrous Compounds / Q000494:pharmacology; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects / Q000235:genetics; D033862:Iron-Binding Proteins; D010100:Oxygen / Q000378:metabolism; D012475:Salmonella / Q000187:drug effects* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012988:Soil Microbiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
D001426:Bacterial Proteins; D005290:Ferric Compounds; D005296:Ferrous Compounds; D033862:Iron-Binding Proteins; C409039:PmrB protein, bacteria; D014157:Transcription Factors; C081902:pmrA protein, Bacteria; D010100:Oxygen