Courtney Aldrich, PhD

A primary objective of our research is to design new antibacterial agents based on novel mechanisms of action. Currently, all clinically used antibiotics act by one of a limited number of mechanisms (e.g. inhibition of protein synthesis, DNA synthesis, cell-wall synthesis, and RNA transcription). We utilize available data from experimental genetic approaches to identify candidate bacterial targets. In cases where the structure and enzymology of the bacterial enzyme is known, we rationally design substrate mimics or transition-state inhibitors. However, for many potential targets there is inadequate structural information available to permit such a structure-based drug design approach. In these cases we develop high-throughput-screening (HTS) assays that allow us to identify a lead candidate molecule. Once a small molecule inhibitor is identified against the targeted enzyme we then apply medicinal chemistry efforts to methodically optimize the inhibitor scaffold. Structure- and/or ligand-based computational approaches are employed to rationalize activity data in order to refine inhibitor design. At an early stage we also test for antibacterial activity against the targeted organism(s) since whole-cell activity is a composite of binding affinity, membrane permeability, and stability. Additionally drug properties of our inhibitors are evaluated using a variety of in vitro assays to examine toxicity, absorption, and metabolism.

PubMed

• Bidwell, Philip A. A., Yuen, Samantha L. L., Li, J., Berg, K., Rebbeck, Robyn T. T., Aldrich, Courtney C. C., Roopnarine, O., Cornea, Razvan L. L., & Thomas, David D. D. (2022). A Large-Scale High-Throughput Screen for Modulators of SERCA Activity. BIOMOLECULES, 12(12). doi: 10.3390/biom12121789
• Ratnapriya, S., Braun, A. R., Benet, H. C., Carlson, D., Ding, S., Paulson, C. N., Mishra, N., Sachs, J. N., Aldrich, C. C., Finzi, A., & Herschhorn, A. (2022). Broad Tricyclic Ring Inhibitors Block SARS-CoV-2 Spike Function Required for Viral Entry. ACS INFECTIOUS DISEASES. doi: 10.1021/acsinfecdis.1c00658
• Cole MS, Howe MD, Buonomo JA, Sharma S, Lamont EA, Brody SI, Mishra NK, Minato Y, Thiede JM, Baughn AD, Aldrich CC. Cephem-Pyrazinoic Acid Conjugates: Circumventing Resistance in Mycobacterium tuberculosis. Chemistry. 2022 Sep 12;28(51):e202200995. doi: 10.1002/chem.202200995. Epub 2022 Jul 27. PMID: 35697660; PMCID: PMC9474573.
• Rebbeck, R. T., Berg, K., Evans, G. M., Schwarz, J., Trask, J. R., McGurran, L. M., Aldrich, C. C., Bers, D. M., Thomas, D. D., & Cornea, R. L. (2022). FRET assays for RyR-targeted drug discovery platforms (3rd ed., vol. 121, pp. 174A-174A). BIOPHYSICAL JOURNAL.
• Lan T, Ganapathy US, Sharma S, Ahn YM, Zimmerman M, Molodtsov V, Hegde P, Gengenbacher M, Ebright RH, Dartois V, Freundlich JS, Dick T, Aldrich CC. Redesign of Rifamycin Antibiotics to Overcome ADP-Ribosylation-Mediated Resistance. Angew Chem Int Ed Engl. 2022 Nov 7;61(45):e202211498. doi: 10.1002/anie.202211498. Epub 2022 Oct 12. PMID: 36222275; PMCID: PMC9633546.
• Hegde, Pooja V. D., Howe, M. D., Zimmerman, M., Boshoff, Helena L. M., Sharma, S., Remache, B., Jia, Z. D., Pan, Y., Baughn, A. C., Dartois, V., & Aldrich, C. (2022). Synthesis and biological evaluation of orally active prodrugs and analogs of para-aminosalicylic acid (PAS). EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 232. doi: 10.1016/j.ejmech.2022.114201
• Okawa, R., Aldrich, C. C., & Ichikawa, S. (2022). Total synthesis of pseudouridimycin and its epimer via Ugi-type multicomponent reaction. CHEMICAL COMMUNICATIONS, 58(57), 7956-7959. doi: 10.1039/d2cc02442j
• Lindsley CW, Liotta DC, Aldrich CC. A Virtual Collection Focused on Antifungal Drug Discovery. ACS Infect Dis. 2022 Mar 11;8(3):399. doi: 10.1021/acsinfecdis.2c00018. Epub 2022 Feb 4. PMID: 35119257.
• Hegde PV, Aragaw WW, Cole MS, Jachak G, Ragunathan P, Sharma S, Harikishore A, Grüber G, Dick T, Aldrich CC. Structure activity relationship of pyrazinoic acid analogs as potential antimycobacterial agents. Bioorg Med Chem. 2022 Nov 15;74:117046. doi: 10.1016/j.bmc.2022.117046. Epub 2022 Oct 7. PMID: 36228522.
• Pujari, V., Rozman, K., Dhiman, R. K., Aldrich, C. C., & Crick, D. C. (2022). Mycobacterial MenG: Partial Purification, Characterization, and Inhibition. ACS INFECTIOUS DISEASES. doi: 10.1021/acsinfecdis.2c00190
• Aldrich, C. C., Calderon, F., Conway, S. J., He, C., Hooker, J. M., Huryn, D. M., Lindsley, C. W., Liotta, D. C., & Muller, C. E. (2022). Virtual Special Issue: Epigenetics 2022 (10th ed., vol. 8, pp. 1975-1980). ACS INFECTIOUS DISEASES. doi: 10.1021/acsinfecdis.2c00434
• Saw, W.-G., Leow, C. Y., Harikishore, A., Shin, J., Cole, M. S., Aragaw, W. W., Ragunathan, P., Hegde, P., Aldrich, C. C., Dick, T., & Gruber, G. (2022). Structural and Mechanistic Insights into Mycobacterium abscessus Aspartate Decarboxylase PanD and a Pyrazinoic Acid-Derived Inhibitor. ACS INFECTIOUS DISEASES, 8(7), 1324-1335. doi: 10.1021/acsinfecdis.2c001331324
• Cole MS, Hegde PV, Aldrich CC. β-Lactamase-Mediated Fragmentation: Historical Perspectives and Recent Advances in Diagnostics, Imaging, and Antibacterial Design. ACS Infect Dis. 2022 Oct 14;8(10):1992-2018. doi: 10.1021/acsinfecdis.2c00315. Epub 2022 Sep 1. PMID: 36048623.
• Hammerstad, T. A., Hegde, Pooja, V, Wang, K. J., & Aldrich, C. C. (2022). Chemoselective Reduction of Tertiary Amides by 1,3-Diphenyl-disiloxane (DPDS). SYNTHESIS-STUTTGART, 54(09), 2205-2212. doi: 10.1055/a-1709-3426
• Schultz JR, Costa SK, Jachak GR, Hegde P, Zimmerman M, Pan Y, Josten M, Ejeh C, Hammerstad T, Sahl HG, Pereira PM, Pinho MG, Dartois V, Cheung A, Aldrich CC. Identification of 5-(Aryl/Heteroaryl)amino-4-quinolones as Potent Membrane-Disrupting Agents to Combat Antibiotic-Resistant Gram-Positive Bacteria. J Med Chem. 2022 Oct 27;65(20):13910-13934. doi: 10.1021/acs.jmedchem.2c01151. Epub 2022 Oct 11. PMID: 36219779; PMCID: PMC9826610.
• Poudel TN, Panda S, Orimoloye M, Hegde P, Aldrich CC. 1'-Cyano Intermediate Enables Rapid and Stereoretentive Access to 1'-Modified Remdesivir Nucleosides. J Org Chem. 2022 Nov 4;87(21):14452-14462. doi: 10.1021/acs.joc.2c01897. Epub 2022 Oct 12. PMID: 36223099.
• Escalante DE, Aldrich CC, Ferguson DM. Parameterization and Application of the General Amber Force Field to Model Fluoro Substituted Furanose Moieties and Nucleosides. Molecules. 2022 Apr 19;27(9):2616. doi: 10.3390/molecules27092616. PMID: 35565967; PMCID: PMC9101125.
• Zhang, J., Singh, D. P., Ko, C. Y., Nikolaienko, R., Yuen, Siobhan M. Wong King, Schwarz, J. A., Treinen, L. M., Tung, C.-C., Rozman, K., Svensson, B., Aldrich, C. C., Zima, Aleksey, V, Thomas, D. D., Bers, D. M., Launikonis, B. S., Van Petegem, Filip, & Cornea, R. L. (2022). Cardiac ryanodine receptor N-terminal region biosensors identify novel inhibitors via FRET-based high-throughput screening. JOURNAL OF BIOLOGICAL CHEMISTRY, 298(1). doi: 10.1016/j.jbc.2021.101412

• ​​​​​​Membrane-Active Anti-Bacterial Compounds and Uses Thereof,  Issued: September 9, 2022
• Next-Generation Remdesivir Antivirals, Issued: August 4, 2022