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Our infectious disease program mainly entails the development of new treatments for tuberculosis (TB), which is still a major health problem throughout the world. Some current projects in this field are summarized below.
b-Lactam antibiotics have long been thought to be ineffective against Mtb. Our group is interested in finding ways to repurpose these long-established and indispensable scaffolds for the treatment of tuberculosis. In collaboration with Carl Nathan and coworkers we have developed novel cephalosporins that are selectively active against Mtb under non-replicating conditions (a model for Mtb that is dormant in macrophages). Compounds within this series are able to inhibit non-replicating Mtb with potencies as low as 0.88 µg/mL, while having no effect on mammalian cells or macrophages.
MIC90 non-replicating Mtb = 0.88 µg/mL
MIC90 replicating Mtb > 100 µg/mL
LD50 in HepG2 >100 µg/mL
In collaboration with Carl Nathan (Weill Cornell), James Sacchettini (Texas A&M), and others, we are seeking to develop inhibitors of 4’-phosphopantetheinyl transferase (PptT), a long-sought drug target in infectious disease. PptT catalyzes the acylation of carrier proteins as a part of the synthesis of virulence factors and cell wall lipids present in the Mtb cell wall. Compound 8918, shown below, inhibits PptT with an IC50 of 2.5 µM and has a MIC90 against wild-type Mtb of 3.1 µM.
MIC90 H37Rv = 3.1 µM
IC50 PptT = 2.5 µM
Following this work, we developed dual-pharmacophore cephalosporins that contain a pyrithione warhead. These compounds are active against both replicating and nonreplicating Mtb. Nucleophilic attack on the b-lactam prompts the ejection of pyrithione, which is toxic to Mtb.
In addition to Mtb inhibitors, we have also improved upon a key tool compound 5-amino-6-D-ribitidylaminouracil (5-A-RU), which is required for the study of mucosal-associated invariant T (MAIT) cells, a cell subtype believed to play a role in antibacterial immunity. A major issue with 5-A-RU is that it is unstable upon storage. We were able to overcome this stability issue by preparing the HCl salt of the compound, which has improved stability. Since our synthesis of the stabilized 5-A-RU, the compound has been sent to labs around the world for the study of MAIT cells.
important tool for the visualization of MAIT cells
Outside of tuberculosis, we have done work with antivirals which are now being independently pursued by lab alumnus Jennifer Golden (University of Wisconsin-Madison).
Suggestions for further reading
Opposing reactions in coenzyme A metabolism sensitize Mycobacterium tuberculosis to enzyme inhibition
New Cephalosporins that are Active on Non-replicating Mycobacterium tuberculosis
Dual Pharmacophore cephalosporins with Pyrithione Warhead
Synthesis and Characterization of 5-Amino-6-D-ribitylaminouracil (5-A-RU)
Respiratory Syncytial Virus Inhibitors
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