Identification of novel antimicrobials using a live-animal infection model

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Abstract
The alarming increase of antibiotic-resistant bacterial pathogens points to the need for novel therapeutic approaches to combat infection. To discover novel antimicrobials, we devised a screen to identify compounds that promoted the survival of the model laboratory nematode Caenorhabditis elegans infected with the human opportunistic pathogen Enterococcus faecalis . E. faecalis colonizes the nematode intestinal tract, forming a persistent lethal infection. Infected nematodes were rescued by antibiotic treatment in a dose-dependent manner, and antibiotic treatment markedly reduced the number of bacteria colonizing the nematode intestine. To facilitate high throughput screening of compound libraries, we adapted a previously developed agar-based C. elegans - E. faecalis infection assay so that it could be carried out in liquid medium in standard 96-well microtiter plates. We used this simple infection system to screen 6,000 synthetic compounds and 1,136 natural product extracts. We identified 16 compounds and 9 extracts that promoted nematode survival. Some of the compounds and extracts inhibited E. faecalis growth in vitro , but, in contrast to traditional antibiotics, the in vivo effective dose of many of these compounds was significantly lower than the minimum inhibitory concentration needed to prevent the growth of E. faecalis in vitro . Moreover, many of the compounds and extracts had little or no affect on in vitro bacterial growth. Our findings indicate that the whole-animal C. elegans screen identifies not only traditional antibiotics, but also compounds that target bacterial virulence or stimulate host defense.