The rise of
antibiotic-resistant bacteria is among the biggest challenges in human and veterinary medicine. One of the major factors that contributes to resistance is use of frontline clinical
antibiotics in veterinary practices. To avoid this problem, searching for antimicrobials aimed at veterinary applications is becoming especially important. Thiopeptide
micrococcin P1 and leaderless
peptide EntEJ97s are two different
bacteriocins that are very active against many gram-positive bacteria; however, sensitive bacteria can rapidly develop resistance towards those
bacteriocins. To overcome this problem, we searched for synergy between those
bacteriocins and conventional
antibiotics against methicillin-resistant Staphylococcus pseudintermedius (MRSP): a common pathogen in animal skin
infections. The two
bacteriocins acted synergistically with each other and with
penicillin G against MRSP clinical isolates in both planktonic and biofilm assays; they also prevented resistance development. The therapeutic potential was further validated in a murine skin
infection model that showed that a combination of
micrococcin P1, EntEJ97s and
penicillin G reduced cell-forming units of MRSP by 2-log10 CFU/g. Taken together, our data show that a combination of
bacteriocins with conventional
antibiotics can not only prevent resistance development but also pave the way to revitalize some old, less useful
antibiotics, such as
penicillin, which by itself has no effect on methicillin-resistant pathogens.