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.

• antibiotics
• tuberculosis
• synthesis
• enzymology

PubMed

• Wang, X., Zeng, Y., Sheng, Li., Larson, P., Liu, X., Zou, X., Wang, S., Guo, K., Ma, C., Zhang, G., Cui, H., Ferguson, D. M., Li, Y., Zhang, J., Aldrich, C. C. A Cinchona Alkaloid Antibiotic that Appears to Target ATP Synthase in Streptococcus pneumoniae. J Med Chem 2018, 62 (5), 2305-2332. doi: 10.1021/acs.jmedchem.8b01353
• Bockman, M. R., Engelhart, C. A., Dawadi, S., Larson, P., Tiwari, D., Ferguson, D. M., Schnappinger, D., Aldrich, C. C. Avoiding Antibiotic Inactivation in Mycobacterium tuberculosis by Rv3406 through Strategic Nucleoside Modification. ACS Infect Dis 2018, 4 (7), 1102-1113. doi: 10.1021/acsinfecdis.8b00038
• Dawadi, S., Boshoff, H. I.M., Park, S. W., Schnappinger, D., Aldrich, C. C. Conformationally Constrained Cinnolinone Nucleoside Analogues as Siderophore Biosynthesis Inhibitors for Tuberculosis. ACS Med Chem Lett 2018, 9 (4), 386-391. doi: 10.1021/acsmedchemlett.8b00090
• Eiden, C. G., Maize, K. M., Finzel, B. C., Lipscomb, J. D., Aldrich, C. C. Rational Optimization of Mechanism-based Inhibitors through Determination of the Microscopic Rate Constants of Inactivation. J Am Chem Soc 2017, 139 (21), 7132-7135. doi: 10.1021/jacs.7b00962
• Fiers, W. D., Dodge, G. J., Sherman, D. H., Smith, J. L., Aldrich, C. C. Vinylogous Dehydration by a Polyketide Dehydratase Domain in Curacin Biosynthesis. J Am Chem Soc 2016, 138 (49) 16024-16036. doi: 10.1021/jacs.6b09748

• Aldrich, C. C., “Antibacterial Agents,” (a) US Patent Appl. 0293666, filed Nov. 27, 2008; (b) EP Patent Appl. 1960518, filed Nov. 27, 2008; (c) PCT Intl. Patent Appl. PCT/US2006/046433, filed Jun 12, 2006, published June 14, 2007; (d) US Prov. Patent Appl. 60.742,729, filed Dec 6, 2005.
• Aldrich, C. C.; Beck, B. J.; Gupte, A., “Antibiotic Triazole Derivatives of 5’-O-[N-(Salicyl)sulfamoyl] adenosine and Methods of Using Same” US Prov. Patent Appl. 61/112,418, filed Nov 7, 2008.
• Aldrich, C. C.; Grimes, K.; Gupte, A. "Antibacterial FadD Inhibitor Compounds and Methods Treatment Using Same" US Prov. Patent Appl. 61/149,902, filed Feb 4, 2009.