Projects

Discovery of New Antibiotics


Identifying New Drug Targets for M. tuberculosis and Gram Negative Pathogens:

              

Image taken from Goldberg, D. E.; Siliciano, R. F.; Jacobs Jr., W. R. Cell 2012148, 1271 

The Aldrich group seeks out new targets for drug development in order to overcome drug resistance in difficult-to-treat infectious diseases. Our primary focus is on the identification and inhibition of novel drug targets in Mtb.

Selected Publications: 

  • Kim, J-H.; O’Brien, K. M.; Sharma, R.; Boshoff, H. I.; Rehren, G.; Chakraborty, S.; Wallach, J. B.; Monteleone, M.; Wilson, D. J.; Aldrich, C. C.; Barry, C. E.; Rhee, K.; Ehrt, S.; Schnappinger, D.* A Novel Genetic Switch Identifies the Mycobacterium tuberculosis NAD Synthetase as a Target for the Development of Improved Tuberculosis Chemotherapies. Proc. Natl. Acad. Sci USA 2013110, 19095–19100. DOI:10.1073/pnas.1315860110
  • Duckworth, B. P.; Nelson, K. M.; Aldrich, C. C.* Adenylating Enzymes in Mycobacterium tuberculosis as Drug Targets. Curr. Top. Med. Chem. 201212, 766–796. DOI: 10.2174/156802612799984571

Inhibition of Siderophore Biosynthesis:

Siderophores are iron-chelating molecules that are synthesized by many bacteria to collect iron from the host. We've identified multiple druggable targets in the siderophore biosynthetic pathway of Mtb and have rationally designed inhibitors that act as transition-state inhibitors and/or bisubstrate inhibitors. 

Selected Publications: 

  • Engellhart, C. A.; Aldrich, C. C. Synthesis of Chromone, Quinolone, and Benzoxazinone Sulfonamide Nucleosides as Conformationally Constrained Inhibitors of Adenylating Enzymes Required for Siderophore Biosynthesis. J. Org. Chem. 201378, 7470–7481. DOI: 10.1021/jo400976f
  • Neres, J.; Labello, N. P.; Somu, R. V.; Boshoff, H. I.; Wilson, D. J.; Vannada, J.; Chen, L.; Barry, C. E. 3rd; Bennett, E. M.; Aldrich, C. C.* Inhibition of Siderophore Biosynthesis in Mycobacterium tuberculosis with Nucleoside Bisubstrate Analogues: Structure Activity Relationships of the Nucleobase Domain of 5’-O-[N-(Salicyl)sulfamoyl]adenosine. J. Med. Chem. 200851, 5349–5370. DOI: 10.1021/jm800567v

Inhibition of Biotin Synthesis and Metabolism:

We have identified and studied multiple drug targets surrounding biotin synthesis and metabolism in MtbInhibition of biotin synthesis or utilization has been shown to be bactericidal to Mtb, allowing for development of a drug that can kill the latent Mtb that is present in nearly 1/3 of the world’s population.  

Selected Publications: 

  • Shi, C.; Aldrich, C. C.* Synthesis of Mechanism-Based Inhibitors of the Aminotransferase BioA Involved in Biotin Biosynthesis as Potential Antibacterial Agents. J. Org. Chem. 201277, 6051–6058. DOI: 10.1021/jo3008435
  • Duckworth, B. P.; Geders, T. W.; Tiwari, D.; Boshoff, H. I.; Sibbald, P. A.; Barry, C. E. 3rd; Schnappinger, D.; Finzel, B. C.; Aldrich, C. C.* Inhibition of Biotin Protein Ligase from Mycobacterium tuberculosis. Chem. Biol.2011, 18, 1432–1441. DOI: 10.1016/j.chembiol.2011.08.013

Prodrug Design to Better Deliver Anti-Tuberculosis Agents:

While working to create our own novel anti-TB agents, we also try to improve already-existing anti-TB agents to improve their pharmacokinetic (PK) and pharmacodynamic (PD) properties. 

Selected Publications: 

  • Teitelbaum, A. M.; Meissner, A.; Wong, C. A.; Aldrich, C. C.*; Remmel, R. P.* Synthesis, pH-Dependent, and Plasma Stability of Meropenem Prodrugs for Drug-Resistant Tuberculosis. Bioorg. Med. Chem. 201321, 5605–5617. DOI: 10.1016/j.bmc.2013.05.024

Screening Campaigns:

In an effort to generate antibiotic agents, the Aldrich group utilizes screening campaigns against many of our drug targets.Both high-throughput screening (HTS) and fragment-based screening (FBS) techniques have been used to identify new scaffolds for inhibitors.  

        Selected Publications: 

  • Dai, R.; Wilson, D. J.; Geders, T. W.; Aldrich, C. C.; Finzel, B. C.* Inhibition of Mycobacterium tuberculosisTransaminase BioA by Aryl Hydrazines and Hydrazides. ChemBioChem201415, 575–586. DOI: 10.1002/cbic.20130074
  • Vasan, M.; Neres, J.; Williams, J.; Wilson, D. J.; Teitelbaum, A. M.; Remmel, R. P.; Aldrich, C. C.* Inhibitors of the Salicylate Synthase (MbtI) from Mycobacterium tuberculosis Discovered by High-Throughput Screening.Chemmedchem20105, 2079–2087. DOI: 10.1002/cmdc.201000275

 

Exploration of Natural Product Biosynthesis


Probes of Adenylating Domains in Non-Ribosomal Peptide and Polyketide Synthetases: 

              

The Aldrich group readily collaborates to understand more about the mechanism and structural specificity of non-ribosomal peptide synthetases (NRPS) and polyketide synthestases (PKS). We synthesize probes that mimic transition states, starting materials, products, and bisubstrates to understand more about these systems. 

Selected Publications: 

  • Zhang, K.; Nelson, K. M.; Bhuripanyo, K.; Grimes, K. D.; Zhao, B.; Aldrich, C. C.*; Yin, J.* Engineering the Substrate Specificity of the DhbE Adenylation Domain by Yeast Cell Surface Display Chem. Biol. 201320, 92–101. DOI: 10.1016/j.chembiol.2012.10.020
  • Mitchell, C. A.; Shi, C.; Aldrich, C. C.; Gulick, A. M.* The Structure of PA1221, a Non-Ribosomal Peptide Synthetase containing Adenylation and Peptidyl Carrier Protein Domains. Biochemistry 201251, 3252–3263. DOI: 10.1021/bi300112e

 

Developing New Methods to Enable Medicinal Chemists


Organic Chemistry:

Medicinal chemistry relies on fundamental organic chemistry in order to synthesize medicinally relevant molecules. While our group's primary focus is not the development of organic methodology, we strive to find new (and better) ways to form the bonds that make up our molecules. 

        Selected Publications: 

  • Shi, C.; Aldrich, C. C.* Efficient Pd-Catalyzed Coupling of Tautomerizable Heterocycles with Terminal Alkynes via C-OH Bond Activation Using PyBroP. Org. Lett. 201012, 2286–2289. DOI: 10.1021/ol100657n
  • Grimes, K. D.; Gupte, A.; Aldrich, C. C.* Copper(II)-Catalyzed Conversion of Aryl/Heteroaryl Boronic acids, -Boronates, and –Trifluoroboronates to the Corresponding Azides: Substrate Scope and Limitations. Synthesis 2010, 1441–1448. DOI: 10.1055/s-0029-1218683

Assay Development:

In order to be pioneers in antibiotic discovery, we need to be able to quantitatively evaluate new antibiotic agents with in vitro assays. As we generally pursue novel targets, assay development has not been previously performed and is thus necessary for compound evaluation. The Aldrich group also performs specialized assay development for high-throughput screening (HTS) campaigns.

Selected Publications: 

  • Wilson, D. J.; Shi, C.; Duckworth, B. P.; Murtta, J. M.; Sham, Y. Y.; Thomas, D. D.; Aldrich, C. C.* A Continuous Fluorescence Displacement Assay for BioA: An Enzyme Involved in Biotin Biosynthesis. Analytical Biochem. 2011416, 27–38. DOI: 10.1016/j.ab.2011.05.003
  • Wilson, D. J.; Aldrich, C. C.* A Continuous Kinetic Assay for Adenylation Enzyme Activity and Inhibition.Analytical Biochem. 2010, 404, 56–63. DOI: 10.1016/j.ab.2010.04.033