Abstract: Methods for treatment of antibiotic-resistant and multi-drug resistant bacterial infections are provided. The methods comprise administration of compositions which mimic plasmid incompatibility in bacteria, resulting in their sensitization to previously resistant drugs. Also provided herein are methods for screening compositions for the ability to mimic plasmid incompatibility by inhibiting Rep protein or by destabilizing RNA/RNA stem loop “kissing” structures. The invention also encompasses compositions identified by the screening methods disclosed herein.