Publication Date:
2010-11-06
Description:
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial beta-glucuronidases that reactivate the drug in the gut. We sought to target these enzymes without killing the commensal bacteria essential for human health. Potent bacterial beta-glucuronidase inhibitors were identified by high-throughput screening and shown to have no effect on the orthologous mammalian enzyme. Crystal structures established that selectivity was based on a loop unique to bacterial beta-glucuronidases. Inhibitors were highly effective against the enzyme target in living aerobic and anaerobic bacteria, but did not kill the bacteria or harm mammalian cells. Finally, oral administration of an inhibitor protected mice from CPT-11-induced toxicity. Thus, drugs may be designed to inhibit undesirable enzyme activities in essential microbial symbiotes to enhance chemotherapeutic efficacy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110694/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3110694/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wallace, Bret D -- Wang, Hongwei -- Lane, Kimberly T -- Scott, John E -- Orans, Jillian -- Koo, Ja Seol -- Venkatesh, Madhukumar -- Jobin, Christian -- Yeh, Li-An -- Mani, Sridhar -- Redinbo, Matthew R -- CA127231/CA/NCI NIH HHS/ -- CA98468/CA/NCI NIH HHS/ -- R01 CA127231/CA/NCI NIH HHS/ -- R01 CA127231-01A2/CA/NCI NIH HHS/ -- R01 CA127231-02/CA/NCI NIH HHS/ -- R01 CA127231-03/CA/NCI NIH HHS/ -- R01 CA161879/CA/NCI NIH HHS/ -- R01 DK073338/DK/NIDDK NIH HHS/ -- New York, N.Y. -- Science. 2010 Nov 5;330(6005):831-5. doi: 10.1126/science.1191175.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21051639" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Antineoplastic Agents, Phytogenic/metabolism/*toxicity
;
Bacteria, Anaerobic/drug effects
;
Camptothecin/*analogs & derivatives/metabolism/toxicity
;
Cell Line, Tumor
;
Colon/drug effects/microbiology/pathology
;
Crystallography, X-Ray
;
Diarrhea/prevention & control
;
Drug Evaluation, Preclinical
;
Enzyme Inhibitors/chemistry/metabolism/*pharmacology
;
Escherichia coli/enzymology
;
Escherichia coli Proteins/antagonists & inhibitors/chemistry/isolation &
;
purification/metabolism
;
Female
;
Glucuronidase/*antagonists & inhibitors/chemistry/isolation &
;
purification/metabolism/*pharmacology
;
Humans
;
Intestinal Mucosa/drug effects/microbiology/pathology
;
Mice
;
Mice, Inbred BALB C
;
Models, Molecular
;
Prodrugs/metabolism/toxicity
;
Protein Conformation
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
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