Drug Discovery Research

Sarka Beranova-Giorgianni, Ph.D.
Associate Professor
Department of Pharmaceutical Sciences
881 Madison Avenue, Room 445
Memphis, TN 38163
Phone: 901-448-5433
Email: sberanova@uthsc.edu 

Education:

• D., University of Akron, Akron, Ohio, Analytical chemistry
• S., Prague Institute of Chemical Technology, Prague, Czechoslovakia, Organic chemistry

Research Specialty:

Bioanalytical chemistry; biological mass spectrometry; qualitative and quantitative proteomics; targeted protein and phosphoprotein identification/characterization.

Research Interests:

My long-term research interests focus on the application of high-end biological mass spectrometry and bioinformatics technologies for qualitative and quantitative characterization of complex biological systems in health and disease. My laboratory houses a cutting-edge high-resolution LC-MS/MS instrument (Waters Synapt G2-Si) and advanced bioinformatics tools, including the Progenesis QIP software. Our team is currently applying targeted and global-scale strategies to examination of the effects of oxidative stress on the molecular machinery in retinal pigment epithelium (RPE) in vitro and in vivo. The main goal of this research is to bring new mechanistic insights into RPE dysfunction in age-related macular degeneration (AMD), and to identify new targets to be exploited for development of therapeutic interventions to halt disease progression. In the bioanalytical area, we focus on development of new and improved workflows for deep quantitative proteome profiling, proximity proteomics, and phosphoproteomics.

 

Laboratory Members:

Sarka Beranova-Giorgianni, PhD (PI)
Diwa Koirala, Graduate student 

Collaborators:

Francesco Giorgianni, Ph.D. UTHSC COP Department of Pharmaceutical Sciences
Marko Radic, Ph.D. UTHSC COM Department of Microbiology, Immunology and Biochemistry
R.K. Rao, Ph.D. UTHSC COM Department of Physiology 

Within the general theme of oxidative stress and RPE dysfunction, we focus on investigation of the mechanistic roles of scavenger receptors in mediating the effects of oxidized lipoproteins (oxLDL) on the retinal pigment epithelium (RPE).  We are currently pursuing two directions: (1) We are testing the hypothesis that response of RPE to oxidized lipoproteins includes production of extracellular vesicles (EVs) carrying molecular cargo (mRNA and proteins), which affects response of proximal RPE to oxidative stress. We are using global-scale bioanalytical strategies to characterize the molecular constituents in the EVs and pinpoint components responsible for EV-mediated effects on proximal cells.  (2) We are investigating the retinal proteomes in mouse models of AMD to identify protein networks associated with age-related progression of oxidative stress-induced tissue damage.

1. Iannaccone, A.; Hollingsworth, T.J.; Koirala, D.; New, D.D.; Lenchik, N.; Beranova-Giorgianni, S.; Gerling, I.C.; Radic, M.Z.; Giorgianni, F. Retinal pigment epithelium and microglia express the CD5 antigen-like protein, a novel autoantigen in age-related macular degeneration. Exp. Eye. Res. 155, 64-74, 2017.
2. Giorgianni F, Beranova-Giorgianni S. Phosphoproteome Discovery in Human Biological Fluids. Proteomes 4, 37, 2016.
3. Iannaccone, A.; Giorgianni, F.; New, D.D.; Hollingsworth, T.J.; Umfress, A.; Alhatem, A.H.; Neeli, I.; Lenchik, N.I.; Jennings, B.J.; Calzada, J.I.; Satterfield, S.; Mathews, D.; Diaz, R.I.; Harris, T.; Johnson, K.C.; Charles, S.; Kritchevsky, S.B., Gerling, I.C.; Beranova-Giorgianni, S.; Radic, M.Z. Circulating autoantibodies in age-related macular degeneration recognize human macular tissue antigens implicated in autophagy, immunomodulation, and protection from oxidative stress and apoptosis. PLOS ONE 10, e0145323, 2015. 
4. Dong Q, Giorgianni F, Beranova-Giorgianni S, Deng X, O'Meally RN, Bridges D, Park EA, Cole RN, Elam MB, Raghow R. Glycogen synthase kinase-3-mediated phosphorylation of serine 73 targets sterol response element binding protein-1c (SREBP-1c) for proteasomal degradation. Biosci Rep. 36, e00284, 2015.
5. Giorgianni, F.; Koirala, D.; Weber, K.T.; Beranova-Giorgianni, S. Proteome analysis of subsarcolemmal cardiomyocyte mitochondria: a comparison of different analytical platforms. Int. J. Mol. Sci. 15, 9285-9301, 2014.

The Hevener laboratory focuses on preclinical infectious diseases drug discovery, antimicrobial target validation and characterization, and structural mechanisms of bacterial resistance. Current research areas include enzyme targets in the bacterial fatty acid synthesis pathway (FAS-II) and bacterial type 1a topoisomerases. Areas of laboratory expertise include structure- and ligand-based drug discovery, computer-aided drug discovery, protein biochemistry, and structural biology.

Dr. Kirk Hevener is an academic pharmacist and pharmaceutical scientist with research expertise in medicinal chemistry, computational chemistry, protein biochemistry, and structural biology.  Dr. Hevener earned a Bachelor of Science degree in Physical Organic Chemistry from Tennessee State University followed by a PharmD and PhD from the University of Tennessee Health Science Center.  Dr. Hevener completed postdoctoral fellowships at St. Jude Children's Research Hospital and the University of Illinois at Chicago, supported during the latter as an NIH NRSA Fellow.  Dr. Hevener was a junior faculty member at Idaho State University’s College of Pharmacy in Meridian, ID from 2013 to 2017 and has joined the faculty at University of Tennessee, College of Pharmacy in March, 2017.

Contact Information:
881 Madison Ave. Ste 671
Memphis, TN 38163
khevener@uthsc.edu
Office – 901-448-1474
https://www.facebook.com/HevenerLaboratory
https://twitter.com/HevenerLab

Lab Personnel
Fahad Bin Aziz Pavel, Graduate Student (Cd-FabK Project)
Dr. Kristiana Avad, Graduate Student (Fn-FabK Project)
Destiny Okpomo, Pharmacy Student (Fn-FabK Project)
Shaun Wayne, Pharmacy Student (Pg-FabK Project)

Lab Alumni
Dipesh Budhathoki, Lab Alumnus (St. John’s University)
Dr. Jesse A. Jones, Lab Alumnus (University of Michigan)

Collaborators
Dr. Julian Hurdle, Texas A&M Health Science Center, Microbiology & Bacteriology (FabK Projects)
Dr. Dianqing Sun, University of Hawaii at Hilo, Synthetic Medicinal Chemistry (FabK Projects)
Dr. Glen Palmer, UTHSC Dept. of Clinical Pharmacy & Translational Sciences (Antifungal Projects)
Dr. Brian Peters, UTHSC Dept. of Clinical Pharmacy & Translational Sciences (Antifungal Projects)
Dr. Bob Moore, UTHSC Dept. of Pharmaceutical Sciences (Cannabinoid Project)
Dr. Frank Park, UTHSC Dept. of Pharmaceutical Sciences (Cannabinoid Project)

1. Investigation of the FAS-II enzyme, FabK, as a narrow-spectrum, druggable target for C. difficile
Drug-resistant C. difficile infection poses a serious threat to public health and contributes to over 29,000 deaths in the U.S. per year. This research proposes to investigate a key enzyme in the bacterial fatty acid synthesis pathway, enoyl-ACP reductase II (FabK), as a novel, druggable target for selective therapy of C. difficile infection (CDI).

2. Investigation of the FabK enzyme from F. nucleatum as a microbiome sparing target for colorectal cancer.
The bacterium Fusobacterium nucleatum has been associated with human colorectal cancer (CRC) and the eradication of this organism using antibacterials was shown to decrease cancer progression. This research proposal seeks to characterize a narrow-spectrum antibacterial target, the FabK enzyme in F. nucleatum, as a microbiome-sparing drug target for prevention or treatment of colorectal cancer.

3. Microbiota-sparing therapies that eliminate Porphyromonas and Fusobacterium species in periodontal disease
Interactions between the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum play a key role in the exacerbation of periodontal disease. There is a critical need for narrow spectrum antibacterials that selectively eliminate these bacteria, while sparing the beneficial bacteria in the oral cavity. This research proposes to characterize and advance a key enzyme in the bacterial fatty acid synthesis pathway, enoyl-ACP reductase II (FabK), as a narrow spectrum target for antibacterial therapy of periodontal disease.

1. Lowes DJ, Miao J, Al-Waqfi RA, Avad KA, Hevener KE, Peters BM. Identification of Dual-Target Compounds with Antifungal and Anti-NLRP3 Inflammasome Activity. ACS Infect Dis. 2021 Aug 13;7(8):2522-2535. doi: 10.1021/acsinfecdis.1c00270. Epub 2021 Jul 14. PubMed PMID: 34260210.

2. Mugengana AK, Vita NA, Brown Gandt A, Moran K, Agyapong G, Sharma LK, Griffith EC, Liu J, Yang L, Gavrish E, Hevener KE, LaFleur MD, Lee RE. The Discovery and Development of Thienopyrimidines as Inhibitors of Helicobacter pylori That Act through Inhibition of the Respiratory Complex I. ACS Infect Dis. 2021 May 14;7(5):1044-1058. doi: 10.1021/acsinfecdis.0c00300. Epub 2021 Jan 20. PubMed PMID: 33471519; PubMed Central PMCID: PMC8122083.

3. Uz Zaman KA, Wu X, Hu Z, Yoshida W, Hou S, Saito J, Avad KA, Hevener KE, Alumasa JN, Cao S. Antibacterial kaneoheoic acids A-F from a Hawaiian fungus Fusarium sp. FM701. Phytochemistry. 2021 Jan;181:112545. doi: 10.1016/j.phytochem.2020.112545. Epub 2020 Nov 17. PubMed PMID: 33217722; PubMed Central PMCID: PMC7869588.

4. Mitachi K, Kansal RG, Hevener KE, Gillman CD, Hussain SM, Yun HG, Miranda-Carboni GA, Glazer ES, Clemons WM Jr, Kurosu M. DPAGT1 Inhibitors of Capuramycin Analogues and Their Antimigratory Activities of Solid Tumors. J Med Chem. 2020 Oct 8;63(19):10855-10878. doi: 10.1021/acs.jmedchem.0c00545. Epub 2020 Sep 18. PubMed PMID: 32886511; PubMed Central PMCID: PMC7554145.

5. Shen WJ, Deshpande A, Hevener KE, Endres BT, Garey KW, Palmer KL, Hurdle JG. Constitutive expression of the cryptic vanGCd operon promotes vancomycin resistance in Clostridioides difficile clinical isolates. J Antimicrob Chemother. 2020 Apr 1;75(4):859-867. doi: 10.1093/jac/dkz513. PubMed PMID: 31873741; PubMed Central PMCID: PMC7069472.

6. Lowes DJ, Hevener KE, Peters BM. Second-Generation Antidiabetic Sulfonylureas Inhibit Candida albicans and Candidalysin-Mediated Activation of the NLRP3 Inflammasome. Antimicrob Agents Chemother. 2020 Jan 27;64(2). doi: 10.1128/AAC.01777-19. Print 2020 Jan 27. PubMed PMID: 31712208; PubMed Central PMCID: PMC6985747.

7. Lee H, Boyle-Vavra S, Ren J, Jarusiewicz JA, Sharma LK, Hoagland DT, Yin S, Zhu T, Hevener KE, Ojeda I, Lee RE, Daum RS, Johnson ME. Identification of Small Molecules Exhibiting Oxacillin Synergy through a Novel Assay for Inhibition of vraTSR Expression in Methicillin-Resistant Staphylococcus aureus. Antimicrob Agents Chemother. 2019 Sep;63(9). doi: 10.1128/AAC.02593-18. Print 2019 Sep. PubMed PMID: 31209003; PubMed Central PMCID: PMC6709460.

8. Jones JA, Hevener KE. Crystal structure of the 65-kilodalton amino-terminal fragment of DNA topoisomerase I from the gram-positive model organism Streptococcus mutans. Biochem Biophys Res Commun. 2019 Aug 20;516(2):333-338. doi: 10.1016/j.bbrc.2019.06.034. Epub 2019 Jun 14. PubMed PMID: 31204053; PubMed Central PMCID: PMC6626674.

9. Jones JA, Prior AM, Marreddy RKR, Wahrmund RD, Hurdle JG, Sun D, Hevener KE. Small-Molecule Inhibition of the C. difficile FAS-II Enzyme, FabK, Results in Selective Activity. ACS Chem Biol. 2019 Jul 19;14(7):1528-1535. doi: 10.1021/acschembio.9b00293. Epub 2019 Jun 26. PubMed PMID: 31184849; PubMed Central PMCID: PMC6642025.

10. Marreddy RKR, Wu X, Sapkota M, Prior AM, Jones JA, Sun D, Hevener KE, Hurdle JG. The Fatty Acid Synthesis Protein Enoyl-ACP Reductase II (FabK) is a Target for Narrow-Spectrum Antibacterials for Clostridium difficile Infection. ACS Infect Dis. 2019 Feb 8;5(2):208-217. doi: 10.1021/acsinfecdis.8b00205. Epub 2018 Dec 13. PubMed PMID: 30501172; PubMed Central PMCID: PMC6889869.

11. Luna-Tapia A, DeJarnette C, Sansevere E, Reitler P, Butts A, Hevener KE, Palmer GE. The Vacuolar Ca2+ ATPase Pump Pmc1p Is Required for Candida albicans Pathogenesis. mSphere. 2019 Feb 6;4(1). doi: 10.1128/mSphere.00715-18. PubMed PMID: 30728284; PubMed Central PMCID: PMC6365616.

12. Zhang M, Prior AM, Maddox MM, Shen WJ, Hevener KE, Bruhn DF, Lee RB, Singh AP, Reinicke J, Simmons CJ, Hurdle JG, Lee RE, Sun D. Pharmacophore Modeling, Synthesis, and Antibacterial Evaluation of Chalcones and Derivatives. ACS Omega. 2018 Dec 31;3(12):18343-18360. doi: 10.1021/acsomega.8b03174. Epub 2018 Dec 26. PubMed PMID: 30613820; PubMed Central PMCID: PMC6312637.

13. Hevener KE, Pesavento R, Ren J, Lee H, Ratia K, Johnson ME. Hit-to-Lead: Hit Validation and Assessment. Methods Enzymol. 2018;610:265-309. doi: 10.1016/bs.mie.2018.09.022. Epub 2018 Oct 25. PubMed PMID: 30390802.

14. Hevener K, Verstak TA, Lutat KE, Riggsbee DL, Mooney JW. Recent developments in topoisomerase-targeted cancer chemotherapy. Acta Pharm Sin B. 2018 Oct;8(6):844-861. doi: 10.1016/j.apsb.2018.07.008. Epub 2018 Jul 25. Review. PubMed PMID: 30505655; PubMed Central PMCID: PMC6251812.

15. Hevener KE, Santarsiero BD, Lee H, Jones JA, Boci T, Johnson ME, Mehboob S. Structural characterization of Porphyromonas gingivalis enoyl-ACP reductase II (FabK). Acta Crystallogr F Struct Biol Commun. 2018 Feb 1;74(Pt 2):105-112. doi: 10.1107/S2053230X18000262. Epub 2018 Jan 26. PubMed PMID: 29400320; PubMed Central PMCID: PMC5947681.

16. Hevener KE. Computational Toxicology Methods in Chemical Library Design and High-Throughput Screening Hit Validation. Methods Mol Biol. 2018;1800:275-285. doi: 10.1007/978-1-4939-7899-1_13. Review. PubMed PMID: 29934898; PubMed Central PMCID: PMC6088382.