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New Roles for Dithiolopyrrolones in Disrupting Bacterial Metal Homeostasis and Inhibiting Metalloenzymes
Author(s) -
Chan Andrew N.,
Shiver Anthony L.,
Wever Walter J.,
Razvi Sayeeda Zeenat A.,
Traxler Matthew F.
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.766.15
Subject(s) - antimicrobial , escherichia coli , acinetobacter baumannii , chemistry , antibiotic resistance , antibiotics , staphylococcus aureus , microbiology and biotechnology , antibacterial activity , klebsiella pneumoniae , deferiprone , biochemistry , bacteria , biology , gene , pseudomonas aeruginosa , deferoxamine , genetics
Natural products have been a major source of life‐saving antibiotics. Antibiotic resistance is a growing health threat that has created an urgent need for new antimicrobial therapies. Many “old” classes of natural products, discovered in the “golden age” of antibiotics, have been overlooked in part due to a lack of understanding of their mode of actions. The dithiolopyrrolone class of natural products contains a disulfide bond, which our group has shown to be important for potent antimicrobial activity. As a class, these natural products have shown potent activity against a range of microbes, including Escherichia coli , methicillin‐resistant Staphylococcus aureus , Klebsiella pneumoniae , and Acinetobacter baumannii . The dithiolopyrrolones were previously reported to inhibit various in vivo processes such as RNA synthesis and carbon utilization; however, confounding evidence leaves the mechanism unclear. To rectify the activity of the dithiolopyrrolones, we conducted a chemical genomics screen in Escherichia coli, which revealed an unusual mechanism of action – the redistribution of cellular metals and the disruption of cellular metal homeostasis*. Using holomycin as a representative dithiolopyrrolone, we determined that the reduced form of holomycin binds transition metals with high affinity using spectrometric methods. In exploitation of this metal‐chelation activity, we showed that reduced holomycin inhibits the in vitro activity of E. coli zinc‐dependent aldolase, a unique antimicrobial target, as well as the metallo‐®‐lactamase, NDM‐1. Significantly, the spread of NDM‐1 and other metallo‐β‐lactamases has enabled clinical resistance to last‐resort β‐lactams, the carbapenems. The in vitro inhibition of NDM‐1 by holomycin serves as a starting point for the further development of holomycin and analogs for enhanced activity against these targets in vivo . This work links the chemical reactivity of the dithiolopyrrolones through their disulfide bond to their antimicrobial action. Our work shows that dithiolopyrrolones are a privileged scaffold due to their potent redox‐controlled antimicrobial activity, demonstrates the power of chemical genomics in characterizing antibiotic mode of action, and highlights the potential of metal‐chelating natural products in antimicrobial therapy. Support or Funding Information This work was supported by National Institute of Health GM099904‐04 (B.L.). S.Z.A.R is supported by the National Science Foundation Graduate Research Fellowship Program (DGF 1106401).