A study published in Science (2010) describes a method to reduce the toxic side effects of the chemotherapy drug CPT-11 (irinotecan) by inhibiting bacterial β-glucuronidases in the gut. These enzymes reactivate CPT-11 in the intestines, causing severe diarrhea. The researchers identified potent bacterial β-glucuronidase inhibitors through high-throughput screening, which selectively target the bacterial enzyme without affecting mammalian enzymes or harmful bacteria. Crystal structures revealed that the inhibitors bind to a unique "bacterial loop" in the enzyme, which is absent in human versions. Inhibitors were effective against bacterial enzymes in both aerobic and anaerobic conditions but did not harm the bacteria or mammalian cells. Oral administration of an inhibitor protected mice from CPT-11-induced toxicity, reducing diarrhea and intestinal damage. The inhibitors were also effective against other anaerobic bacteria, including Bacteroides vulgatus and Clostridium ramosum. The study shows that targeting bacterial enzymes can enhance chemotherapy efficacy by reducing toxic side effects. The findings suggest that selective inhibition of microbial enzymes could be a promising strategy for improving cancer treatments.A study published in Science (2010) describes a method to reduce the toxic side effects of the chemotherapy drug CPT-11 (irinotecan) by inhibiting bacterial β-glucuronidases in the gut. These enzymes reactivate CPT-11 in the intestines, causing severe diarrhea. The researchers identified potent bacterial β-glucuronidase inhibitors through high-throughput screening, which selectively target the bacterial enzyme without affecting mammalian enzymes or harmful bacteria. Crystal structures revealed that the inhibitors bind to a unique "bacterial loop" in the enzyme, which is absent in human versions. Inhibitors were effective against bacterial enzymes in both aerobic and anaerobic conditions but did not harm the bacteria or mammalian cells. Oral administration of an inhibitor protected mice from CPT-11-induced toxicity, reducing diarrhea and intestinal damage. The inhibitors were also effective against other anaerobic bacteria, including Bacteroides vulgatus and Clostridium ramosum. The study shows that targeting bacterial enzymes can enhance chemotherapy efficacy by reducing toxic side effects. The findings suggest that selective inhibition of microbial enzymes could be a promising strategy for improving cancer treatments.