ABSTRACTWhile diverse antibacterials are available in nature, each possesses their own strengths and limitations. One such antibacterial is colicins, proteinaceous toxins that are produced by strains ofE. colito subvert the growth or viability of otherE. colistrains. Similarly, predatory bacteria, of whichBdellovibrio bacteriovorusis well-known, are microbes that actively predate on and consume other Gram-negative bacterial strains. While they are all quite active as antibacterials, they also present some limitations: rapid resistance development to colicins while predation does not completely kill their prey. Within this study, therefore, we evaluated the impact of two different colicins (colicin B [ColB] and colicin E5 [ColE5]) andB. bacteriovorusHD100 either individually or together against four clinical isolates ofE. colithat are resistant to either colistin or carbapenem. While the ColB and ColE5 were quickly active when used alone, causing a significant loss in viability (>3-log) in susceptible populations after only 3 h, the pathogens always grew afterwards and had final cell densities that were similar with their respective controls. Predation withB. bacteriovorusHD100, in contrast, was most pronounced after 24 h (>3-log reduction in each pathogen viability but never complete). When combined, better killing efficiencies were observed with several of the pathogens, with complete eradication realized for two (<100 viable pathogens per mL). Given the diversity of colicins in nature and the broad-spectrum activities ofB. bacteriovorusstrains, the results presented here suggest there is a massive potential to control pathogens when they are used together.IMPORTANCEThe coupled impact of drug resistance with reduced antibiotic development has placed humankind at a postantibiotic crossroads where antibiotic alternatives are desperately needed. Consequently, we discuss here the combined effectiveness of two vastly different classes of antibacterials, namely, colicins and a predatory bacterium (i.e.,Bdellovibrio bacteriovorusHD100), against two priority pathogenic groups, colistin- and carbapenem-resistant strains ofE. coli. While each is effective in its own manner, these antibacterials also display limitations, i.e., the rapid appearance of mutations that confer resistance to the colicins while predatory bacteria do not completely kill their prey. Here, we show these limitations can be overcome using combined treatments of these antibacterials, with two pathogenicE. colipopulations completely eradicated within 24 h. Given the diversity of colicins and the broad-spectrum activities ofB. bacteriovorusstrains, the results presented here suggests there is a massive potential to control pathogens when they are used together.