Dr. Songping Huang: "Nanomedicine – Development of Novel Nanoparticles to Target the Vulnerability of Iron Metabolism for Treating Bacterial Infections"

Songping Huang
Dr. Songping Huang
Ph.D. Michigan State University, 1993
Professor
330 Integrated Sciences Building
shuang1@kent.edu
330-672-2230
 

Research work in Huang Group is divided into three major areas: (1) rational design and synthesis of small-molecule antimicrobial agents that have different cellular or molecular targets than those of the conventional antibiotics for combating antimicrobial resistance (AMR); (2) harnessing cytotoxicity from ferroptosis for cancer treatment; and (3) development of MRI contrast agents for gastrointestinal (GI) tract imaging.

Antibiotics have underpinned modern medicine for well over 70 years. Their use has reduced childhood mortality, increased life expectancy, made invasive surgery and organ transplant possible, and ensured the safety of cancer chemotherapy, to name just a few. Meanwhile, in response to the widespread use and misuse of antibiotics in humans and animals, bacterial pathogens have accelerated the process of mutation to develop drug resistance to these medicines.  As a result, drug-resistant bacterial pathogens have started to spread faster than the discovery of new antibiotics. It is estimated that more than 30% of clinical isolates of Pseudomonas aeruginosa (P. aeruginosa) from the patients in any given intensive care unit (ICU) or a nursing home are now resistant to three or more antibiotic drugs. The situation is very similar for other pathogenic organisms. It is alarming to note that some strains have become resistant to virtually all the commonly available antimicrobial agents.

We focus on the discovery of new molecules that can act as effective NDH-2 inhibitors to overcome ARM. NDH-2, also known as type II dehydrogenase, is a peripheral membrane protein functioning as an enzyme (EC: 1.6.99.3) to catalyze the electron transfer in respiratory chain of certain pathogenic organisms e.g., Staphylococcus aureus (SA), but not expressed in mammals, hence constituting an ideal target for rational drug design. Since NDH-2 is not a known target of any existing antimicrobial drugs, our drug lead compound 6c exhibits not only unusual potency against SA, but also the remarkable ability to overcome the drug resistance in a number of antibiotic-resistant SA mutant bacteria. Currently, 6c is under preclinical animal studies for development as a topical antimicrobial drug to treat skin and soft-tissue MRSA (i.e., methicillin-resistant staphylococcus aureus) infections, particularly those by the MRSA mutant bacteria that are resistant to mupirocin and fusidic acid, the two widely used topical antibiotics for treating skin and soft-tissue MRSA infections.

 

Development of novel nanoparticles to target the vulnerability of iron metabolism

Ferroptosis is a special type of programmed cell death triggered by cellular dysregulation of iron. We capitalize on ferroptosis as a new mode of action to develop Fe-based metallodrugs for cancer chemotherapy with the aim to improve the selectivity of cytotoxicity in cancerous cells vs. normal cells to reduce toxic side effects of anticancer drugs. Iron is known as a double-edged sword in biology: it is essential for almost all forms of life for their survival, division and growth, yet iron is potentially cytotoxic as dysregulated cellular iron uptake can result in reactive oxygen species (ROS)-triggered cell death from the iron-catalyzed Fenton reaction. Through the judicial selection of lipophilic iron chelators with high affinity for Fe(III) as the ionophores, we have demonstrated that certain octahedral Fe(III) complexes with D3 symmetry have the remarkable ability to transport iron across the cell membrane to trigger intracellular Fenton reaction, which affords potent broad-spectrum in vitro anticancer activity against a plethora of cancer cell lines including the Pt-resistant ovarian cancer cell line. Since the cellular targets and the mode of action of such Fe(III) complexes are drastically different and nonoverlapping with those of cisplatin, they have the distinct ability to overcome Pt resistance in A2780cis ovarian cancer cells. Our work in this area raises the possibility of harnessing ferroptosis to develop Fe-based metallodrugs for cancer chemotherapy.

Lipophilic Fe(III) complex with D3 symmetry

The current commercial contrast agents (CAs) used in MRI are small-molecule Gd3+-chelates that do not have sufficient stability in acidic environment of the stomach and temporal stability when they move through the GI tract, making the development of oral MRI contrast agents based on the platform of Gd3+-complexes problematic. Our group pioneered the use of biocompatible NPs of Prussian blue (PB) and its many analogues as oral contrast agents for MRI applications. Such NPs exhibit extremely high stability in the gastric juice, high r1 relaxivity, low toxicity and high temporal stability, showing great potential for the development of true T1-weighted oral contrast agentsfor MR imaging of the entire GI tract, an unmet clinical need in diagnostic medicine.

Biocompatible NPs of Prussian blue exhibit extremely high stability in the gastric juice, high r1 relaxivity, low toxicity and high temporal stability, showing great potential for the development of true T1-weighted oral contrast agents for MR imaging of the entire GI tract, an unmet clinical need in diagnostic medicine.

Selected Publications:

  1. N. Abeydeera, B. Yu, P. D. Bishnu, M. Kim, S. D. Huang “Harnessing the Toxicity of Dysregulated Iron Uptake for Killing Staphylococcus aureus: Reality or Mirage?” Biomaterials Science (IF=6.843),10, 474-484 (2022). https://doi.org/10.1039/D1BM01743H
  2. Z. Wang, J. Li, B. M. Benin, B. Yu, S. D. Bunge, N. Abeydeera, S. D. Huang, M.-H. Kim “Lipophilic Ga Complex with Broad-Spectrum Antimicrobial Activity and the Ability to Overcome Gallium Resistance in both Pseudomonas aeruginosa and Staphylococcus aureus” Journal Medicinal Chemistry (IF=7.446), 64: 9381-9388 (2021). https://doi.org/10.1021/acs.jmedchem.1c00656
  3. M. S. Kandanapitiye, T. M. Dassanayake, A. C. Dassanayake, J. Shelestak, R. J. Clements, S. D. Huang “K2Mn3[FeII(CN)6]2 NPs with High T1-Relaxivity Attributable to Water Coordination on the Mn(II) Center for Gastrointestinal Tract MR Imaging” Advanced. Healthcare Materials (IF=9.933), 10(20): 2100987 (2021). https://doi.org/10.1002/adhm.202100987
  4. Dyne E, Prakash P, Li J, Yu B, Schmidt T, Huang S, Kim MH. “Mild Magnetic Nanoparticle Hyperthermia Promotes the Disaggregation and Microglia-mediated Clearance of Beta-Amyloid Plaques” Nanomedicine: Nanotechnology, Biology, and Medicine (IF=6.458), 34:102397 (2021). doi.org/10.1016/j.nano.2021.102397; https://pubmed.ncbi.nlm.nih.gov/33857686
  5. Song R, Yu B, Friedrich D, Li J, Shen H, Krautscheid H, Huang SD, Kim MH. “Napthoquinone-derivative as a synthetic compound to overcome the antibiotic resistance of methicillin-resistant S. aureus” Communications Biology (IF=6.268), 3(1):529 (2020). https://www.nature.com/articles/s42003-020-01261-0
  6. Yu B., Wang Z., Almutairi L., Huang S., Kim MH “Harnessing iron oxide nanoparticles towards the improved bactericidal activity of macrophages against Staphylococcus aureus” Nanomedicine: Nanotechnology, Biology, and Medicine (IF=6.458), 24:102158 (2020). https://pubmed.ncbi.nlm.nih.gov/31982615; https://onlinelibrary.wiley.com/doi/abs/10.1002/ange.201713177
  7. Wang Z, Yu B, Alamri H, Yarabarla S, Kim MH, Huang SD “KCa(H2O)2[FeIII(CN)6].H2O nanoparticles as a novel antimicrobial agent for Staphylococcus aureus” Angewandte Chemie Intd ((IF=15.334).) 37:2214-2218 (2018). https://onlinelibrary.wiley.com/doi/abs/10.1002/ange.201713177

 

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