Drug efflux pump inhibitors for the multidrug resistance protein HmrM, a member of the multidrug and toxin extrusion (MATE) family of transporters, were investigated to increase the drug susceptibility of multidrug-resistant bacteria and restore the antimicrobial effect of fluoroquinolones, such as norfloxacin. The lead inhibitor, prepared from the known hMATE1 inhibitor cimetidine, reduced the norfloxacin resistance of HmrM-expressing strains by 92% at non-cytotoxic concentrations in human cells, and multidrug resistance protein MdtK-expressing strains by 86%. These results indicated that the inhibitor is a lead candidate for the development of drugs with a novel mechanism of action against infections caused by multidrug-resistant bacteria that act synergistically with antimicrobial drugs.