Katherine Franz

Overview:

Research in the Franz group is involved in elucidating the structural and functional consequences of metal ion coordination in biological systems. We are particularly interested in understanding the coordination chemistry utilized by biology to manage essential yet toxic species like copper and iron. Understanding these principles further guides our development of new chemical tools to manipulate biological metal ion location, speciation, and reactivity for potential therapeutic benefit. We use a combination of synthesis, spectroscopy, and biochemistry in our work. Please visit our group website to learn more about our research.

Positions:

Chair of the Department of Chemistry

Chemistry
Trinity College of Arts & Sciences

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Professor in the Department of Chemistry

Chemistry
Trinity College of Arts & Sciences

Education:

B.A. 1995

Wellesley College

Ph.D. 2000

Massachusetts Institute of Technology

Grants:

Elucidating the Reactive Species Responsible for the Antifungal Activity of a Metallopeptide

Administered By
Chemistry
Awarded By
National Science Foundation
Role
Principal Investigator
Start Date
End Date

Mapping the Fundamentals of Coordination Chemistry onto Mechanically Activated Pathways

Administered By
Chemistry
Awarded By
American Chemical Society
Role
Principal Investigator
Start Date
End Date

Stimulus-Responsive Agents For Manipulating Cellular Copper

Administered By
Chemistry
Awarded By
National Science Foundation
Role
Principal Investigator
Start Date
End Date

REU Site: Chemistry and Applications of Smart Molecules and Materials at Duke University

Administered By
Chemistry
Awarded By
National Science Foundation
Role
Co-Principal Investigator
Start Date
End Date

BioMetals 2014 Conference at Duke University

Administered By
Chemistry
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
Start Date
End Date

Publications:

Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.

Disulfiram in conjunction with copper has been shown to be a potent anticancer agent. However, disulfiram's therapeutic potential in prostate cancer is hindered by off-target effects due to its reactive and nucleophilic thiol-containing component, diethyldithiocarbamate (DTC). To minimize undesirable reactivity, we have strategically blocked the thiol moiety in DTC with a cleavable p-aminobenzyl (pAB) group linked to peptide substrates recognized by prostate specific antigen (PSA). Here we report the synthesis and evaluation in cancer cell models of two PSA-activatable prodrugs: HPD (Ac-HSSKLQL-pAB-DTC and RPD (RSSYYSL-pAB-DTC). In vitro exposure to PSA was found to trigger activation of HPD and RPD to release diethyldithiocarbamate, and both prodrugs were found to induce toxicity in prostate cancer cells, with HPD showing the most promising selectivity. With copper supplementation, the IC50 of HPD was 1.4 µM in PSA-expressing LNCaP cells, and 11 µM in PC3 cells that do not express PSA. These studies demonstrate the utility of using peptide recognition handles to direct the activity of dithiocarbamate prodrugs for selective cytotoxicity of cancer cells.
Authors
Bakthavatsalam, S; Wiangnak, P; George, DJ; Zhang, T; Franz, KJ
MLA Citation
Bakthavatsalam, Subha, et al. “Dithiocarbamate prodrugs activated by prostate specific antigen to target prostate cancer.Bioorg Med Chem Lett, vol. 30, no. 11, June 2020, p. 127148. Pubmed, doi:10.1016/j.bmcl.2020.127148.
URI
https://scholars.duke.edu/individual/pub1436721
PMID
32253061
Source
pubmed
Published In
Bioorg Med Chem Lett
Volume
30
Published Date
Start Page
127148
DOI
10.1016/j.bmcl.2020.127148

A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc.

Antibacterial drug resistance is a rapidly growing clinical threat, partially due to expression of β-lactamase enzymes, which confer resistance to bacteria by hydrolyzing and inactivating β-lactam antibiotics. The increasing prevalence of metallo-β-lactamases poses a unique challenge, as currently available β-lactamase inhibitors target the active site of serine β-lactamases but are ineffective against the zinc-containing active sites of metallo-β-lactamases. There is an urgent need for metallo-β-lactamase inhibitors and antibiotics that circumvent resistance mediated by metallo-β-lactamases in order to extend the utility of existing β-lactam antibiotics for treating infection. Here we investigated the antibacterial chelator-releasing prodrug PcephPT (2-((((6R,7R)-2-carboxy-8-oxo-7-(2-phenylacetamido)-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)methyl)thio) pyridine 1-oxide) as an inhibitor of New Delhi metallo-β-lactamase 1 (NDM-1). PcephPT is an experimental compound that we have previously shown inhibits growth of β-lactamase-expressing E. coli using a mechanism that is dependent on both copper availability and β-lactamase expression. Here, we found that PcephPT, in addition to being a copper-dependent antibacterial compound, inhibits hydrolysis activity of purified NDM-1with an IC50 of 7.6 μM without removing zinc from the active site and restores activity of the carbapenem antibiotic meropenem against NDM-1-producing E. coli. This work demonstrates that targeting a metal-binding pharmacophore to β-lactamase-producing bacteria is a promising strategy for inhibition of both bacterial growth and metallo-β-lactamases.
Authors
Jackson, AC; Zaengle-Barone, JM; Puccio, EA; Franz, KJ
MLA Citation
Jackson, Abigail C., et al. “A Cephalosporin Prochelator Inhibits New Delhi Metallo-β-lactamase 1 without Removing Zinc.Acs Infectious Diseases, vol. 6, no. 5, May 2020, pp. 1264–72. Epmc, doi:10.1021/acsinfecdis.0c00083.
URI
https://scholars.duke.edu/individual/pub1439769
PMID
32298084
Source
epmc
Published In
Acs Infectious Diseases
Volume
6
Published Date
Start Page
1264
End Page
1272
DOI
10.1021/acsinfecdis.0c00083

Correction to Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria.

Authors
Zaengle-Barone, JM; Jackson, AC; Besse, DM; Becken, B; Arshad, M; Seed, PC; Franz, KJ
MLA Citation
Zaengle-Barone, Jacqueline M., et al. “Correction to Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria.Acs Infectious Diseases, vol. 6, no. 4, Apr. 2020, p. 759. Epmc, doi:10.1021/acsinfecdis.0c00082.
URI
https://scholars.duke.edu/individual/pub1434707
PMID
32153181
Source
epmc
Published In
Acs Infectious Diseases
Volume
6
Published Date
Start Page
759
DOI
10.1021/acsinfecdis.0c00082

Grab 'n Go: Siderophore-Binding Proteins Provide Pathogens a Quick Fix to Satisfy Their Hunger for Iron.

Authors
Gallo, AD; Franz, KJ
MLA Citation
Gallo, Annastassia D., and Katherine J. Franz. “Grab 'n Go: Siderophore-Binding Proteins Provide Pathogens a Quick Fix to Satisfy Their Hunger for Iron.Acs Central Science, vol. 6, no. 4, Apr. 2020, pp. 456–58. Epmc, doi:10.1021/acscentsci.0c00179.
URI
https://scholars.duke.edu/individual/pub1437000
PMID
32341992
Source
epmc
Published In
Acs Central Science
Volume
6
Published Date
Start Page
456
End Page
458
DOI
10.1021/acscentsci.0c00179

A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis.

Infection by the fungal pathogen Cryptococcus neoformans causes lethal meningitis, primarily in immune-compromised individuals. Colonization of the brain by C. neoformans is dependent on copper (Cu) acquisition from the host, which drives critical virulence mechanisms. While C. neoformans Cu+ import and virulence are dependent on the Ctr1 and Ctr4 proteins, little is known concerning extracellular Cu ligands that participate in this process. We identified a C. neoformans gene, BIM1, that is strongly induced during Cu limitation and which encodes a protein related to lytic polysaccharide monooxygenases (LPMOs). Surprisingly, bim1 mutants are Cu deficient, and Bim1 function in Cu accumulation depends on Cu2+ coordination and cell-surface association via a glycophosphatidyl inositol anchor. Bim1 participates in Cu uptake in concert with Ctr1 and expression of this pathway drives brain colonization in mouse infection models. These studies demonstrate a role for LPMO-like proteins as a critical factor for Cu acquisition in fungal meningitis.
Authors
Garcia-Santamarina, S; Probst, C; Festa, RA; Ding, C; Smith, AD; Conklin, SE; Brander, S; Kinch, LN; Grishin, NV; Franz, KJ; Riggs-Gelasco, P; Lo Leggio, L; Johansen, KS; Thiele, DJ
MLA Citation
Garcia-Santamarina, Sarela, et al. “A lytic polysaccharide monooxygenase-like protein functions in fungal copper import and meningitis.Nat Chem Biol, vol. 16, no. 3, Mar. 2020, pp. 337–44. Pubmed, doi:10.1038/s41589-019-0437-9.
URI
https://scholars.duke.edu/individual/pub1428176
PMID
31932719
Source
pubmed
Published In
Nat Chem Biol
Volume
16
Published Date
Start Page
337
End Page
344
DOI
10.1038/s41589-019-0437-9