The antagonistic interactions between a polyvalent phage SaP7 and β-lactam antibiotics on combined therapies

Phage therapy is a promising alternative antibiotic strategy to combat multidrug-resistant bacteria infections. Most studies focus on the synergistic effects, while the antagonistic interactions between phage and antibiotics is rarely studied. Here, we isolated and identified a novel polyvalent phage SaP7, which is capable of infecting multidrug-resistant Salmonella S7 and several E. coli strains. Morphology via electron microscopy showed that SaP7 belonged to the Myoviridae family. Genomic analysis revealed that the genome of SaP7 lacked any genes associated with antibiotic resistance, toxins, lysogeny, and virulence factors. We discovered the antagonism efficacy of SaP7 combined amoxicillin/potassium clavulanate (AMC) in counteracting Salmonella S7 in piglet-models by bacterial loads in feces and tissues. The consistent result as above between SaP7 and amoxicillin (AMX) was further verified in BALB/c mice-models. Furthermore, in vitro, plaque assay and minimum inhibitory concentration (MIC) determinations showed that AMX or AMC or cefepime (FEP) inhibited SaP7 plaque formation respectively and SaP7 decreased bacterial susceptibility of Salmonella S7 to AMX, AMC and FEP. And the negative interference of SaP7 with the bacteriostasis to Salmonella S7 of these three β-lactam antibiotics was observed in planktonic cultures via microtiter plates, but could not prevent the bacteriostasis of high titer of phage or high concentration of antibiotics. Finally, our research suggested that a polyvalent phage SaP7 existed antagonism with several β-lactam antibiotics. It is therefore crucial to fully and cautiously evaluate phage/antibiotic interactions and probable outcomes to avoid antagonistic impacts and failure of antibiotic and phage combination therapy.