Alleviating cancer drug toxicity by inhibiting a bacterial enzyme.
The dose-limiting side effect of the common colon cancer chemotherapeutic CPT-11 is severe diarrhea caused by symbiotic bacterial β-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 β-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 β-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.
Department of Chemistry, University of North Carolina, Chapel Hill, NC 27599, USA.
Bret D
BD
Wallace
Hongwei
H
Wang
Kimberly T
KT
Lane
John E
JE
Scott
Jillian
J
Orans
Ja Seol
JS
Koo
Madhukumar
M
Venkatesh
Christian
C
Jobin
Li-An
LA
Yeh
Sridhar
S
Mani
Matthew R
MR
Redinbo
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism / Q000633:toxicity*; D001421:Bacteria, Anaerobic / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D018360:Crystallography, X-Ray; D003967:Diarrhea / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D005260:Female; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D000077146:Irinotecan; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D011355:Prodrugs / Q000378:metabolism / Q000633:toxicity; D011487:Protein Conformation
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D011355:Prodrugs; C106003:SN38-Glu; D000077146:Irinotecan; D005966:Glucuronidase; D002166:Camptothecin