Two compounds, from among 300,000 candidates screened, kill parasite-supporting bacteria after a single dose in mouse models of filarial diseases - one of the biggest contributors to disability and poverty in the developing world. The compounds wiped out bacteria much faster than standard antibiotics, indicating that short courses of treatment could potentially eradicate filarial worms in patients. Parasitic filarial diseases such as elephantiasis represent a massive and neglected health burden in developing countries and can cause debilitating complications such as disfigurement and blindness. The standard-of-care treatment for filarial worms is a four to six-week course of the antibiotic doxycycline, which targets a symbiotic bacterial species named Wolbachia that sustains the worms' reproduction. However, doxycycline cannot be administered to pregnant women and children, and the long duration of treatment has limited its use in resource-constrained regions. In search of new therapeutic options, Malina Bakowski and colleagues screened over 300,000 small molecules to identify those with activity against Wolbachia. After selecting eight promising candidates, the researchers further optimized their potency and zeroed in on the two highest-performing compounds named CBR417 and CBR490. Both compounds effectively killed over 99% of all Wolbachia bacteria with a single dose in a mouse model of filarial disease without causing toxicity and were superior to a two-week course of doxycycline. Furthermore, a two-week course of a third candidate named CBR715 killed Wolbachia more effectively compared to 42 days of treatment with doxycycline in a mouse model of lymphatic filariasis, suggesting that these compounds could combat a variety of hard-to-treat filarial infections.