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Chatman, Kelly

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Chatman

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Chatman, Kelly

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2013 - 201912020 - 20211

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Author's Publications: search.filters.isAuthorOfPublication.89263338-c3cc-42e0-9b38-ef4346d637b7

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    Predicting and Manipulating Cardiac Drug Inactivation by the Human Gut Bacterium Eggerthella lenta
    (American Association for the Advancement of Science (AAAS), 2013) Haiser, Henry J.; Gootenberg, David; Chatman, Kelly; Sirasani, Gopal; Balskus, Emily; Turnbaugh, Peter
    Despite numerous examples of the effects of the human gastrointestinal microbiome on drug efficacy and toxicity, there is often an incomplete understanding of the underlying mechanisms. Here, we dissect the inactivation of the cardiac drug digoxin by the gut Actinobacterium Eggerthella lenta. Transcriptional profiling, comparative genomics, and culture-based assays revealed a cytochrome-encoding operon up-regulated by digoxin, inhibited by arginine, absent in nonmetabolizing E. lenta strains, and predictive of digoxin inactivation by the human gut microbiome. Pharmacokinetic studies using gnotobiotic mice revealed that dietary protein reduces the in vivo microbial metabolism of digoxin, with significant changes to drug concentration in the serum and urine. These results emphasize the importance of viewing pharmacology from the perspective of both our human and microbial genomes.
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    A Synthetic Antibiotic Class Overcoming Bacterial Multidrug Resistance
    (Springer Science and Business Media LLC, 2021-10-27) Mitcheltree, Matthew; Pisipati, Amarnath; Syroegin, Egor A.; Silvestre, Katherine; Klepacki, Dorota; Mason, Jeremy; Terwilliger, Daniel; Testolin, Giambattista; Pote, Aditya; Wu, Jun Yu Kelvin; Ladley, Richard; Chatman, Kelly; Mankin, Alexander S.; Polikanov, Yury S.; Myers, Andrew
    The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern . For more than five decades, the search for new antibiotics has relied heavily upon the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings . Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, here named iboxamycin. Iboxamycin is effective against ESKAPE-group pathogens including strains expressing Erm and Cfr rRNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins, and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including an unforeseen and unprecedented displacement of the m2/6A2058 nucleotide upon antibiotic binding. In mice, iboxamycin is orally bioavailable, safe, and effective in treating both Gram-positive and Gram-negative bacterial infections, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of rising resistance.