The Suf Iron-Sulfur Cluster Biosynthetic System Is Essential in Staphylococcus aureus, and Decreased Suf Function Results in Global Metabolic Defects and Reduced Survival in Human Neutrophils.
Staphylococcus aureusremains a causative agent for morbidity and mortality worldwide. This is in part a result of antimicrobial resistance, highlighting the need to uncover novel antibiotic targets and to discover new therapeutic agents. In the present study, we explored the possibility that iron-sulfur (Fe-S) cluster synthesis is a viable antimicrobial target. RNA interference studies established that Suf (sulfur mobilization)-dependent Fe-S cluster synthesis is essential inS. aureusWe found thatsufCDSUBwere cotranscribed and thatsuftranscription was positively influenced by sigma factor B. We characterized anS. aureusstrain that contained a transposon inserted in the intergenic space betweensufCandsufD(sufD*), resulting in decreased transcription ofsufSUBConsistent with the transcriptional data, thesufD* strain had multiple phenotypes associated with impaired Fe-S protein maturation. They included decreased activities of Fe-S cluster-dependent enzymes, decreased growth in media lacking metabolites that require Fe-S proteins for synthesis, and decreased flux through the tricarboxylic acid (TCA) cycle. Decreased Fe-S cluster synthesis resulted in sensitivity to reactive oxygen and reactive nitrogen species, as well as increased DNA damage and impaired DNA repair. ThesufD* strain also exhibited perturbed intracellular nonchelated Fe pools. Importantly, thesufD*strain did not exhibit altered exoprotein production or altered biofilm formation, but it was attenuated for survival upon challenge by human polymorphonuclear leukocytes. The results presented are consistent with the hypothesis that Fe-S cluster synthesis is a viable target for antimicrobial development.
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
Christina A
CA
Roberts
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
Hassan M
HM
Al-Tameemi
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
Ameya A
AA
Mashruwala
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
Zuelay
Z
Rosario-Cruz
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
Unnati
U
Chauhan
Department of Microbiology, New York University School of Medicine, New York, New York, USA.
William E
WE
Sause
Department of Microbiology, New York University School of Medicine, New York, New York, USA.
Victor J
VJ
Torres
Department of Animal Sciences, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA.
William J
WJ
Belden
Department of Biochemistry and Microbiology, School of Environmental and Biological Sciences, Rutgers, State University of New Jersey, New Brunswick, New Jersey, USA jmboyd@AESOP.Rutgers.edu.
Jeffrey M
http://orcid.org/0000-0001-7721-3926
JM
Boyd
D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000235:genetics / Q000378:metabolism*; D009504:Neutrophils / Q000382:microbiology*; D010100:Oxygen / Q000378:metabolism; D016372:RNA, Antisense / Q000032:analysis; D026361:Reactive Nitrogen Species / Q000378:metabolism; D013203:Staphylococcal Infections / Q000235:genetics / Q000382:microbiology; D013211:Staphylococcus aureus / Q000235:genetics / Q000378:metabolism* / Q000472:pathogenicity*; D014774:Virulence
D001426:Bacterial Proteins; D007506:Iron-Sulfur Proteins; D016372:RNA, Antisense; D026361:Reactive Nitrogen Species; D010100:Oxygen
Staphylococcus aureus; Suf; cluster; iron; neutrophil; sulfur