Niclosamide is an FDA-approved anthelmintic drug that we and others have shown also has potent antibiotic activity against Gram positive bacteria, with low rates of spontaneous resistance and promising efficacy in Phase II trials against MRSA. However, niclosamide has been reported by several sources to be inactive against Gram negative pathogens. We have shown this is due to efflux of niclosamide via the Gram negative efflux pump TolC, and co-administration of TolC inhibitors renders Gram negatives highly sensitive to niclosamide. Excitingly, niclosamide also synergizes with the outer-membrane permeabilising antibiotics colistin and polymyxin B, viewed as “drugs of last resort” owing to their nephrotoxic side-effects. We will evaluate the ability of niclosamide to increase the potency and safety of these important antibiotics, seek to develop new niclosamide analogs that are not AcrAB-TolC substrates, and advance understanding of the antibacterial mechanisms of niclosamide as well as possible bacterial resistance mechanisms.