Synergistic Antibacterial Effect and Mechanism of Allicin and an Enterobacter cloacae Bacteriophage

ABSTRACT Enterobacter cloacae is a troublesome pathogen causing refractory infections of the lower respiratory tract, urethra and abdominal cavity, endocarditis, osteomyelitis, and neonatal septicemia. It is prone to developing resistance to ordinary antibiotics and has brought a serious problem to clinical treatment. An artful synergistic combination of an antibacterial natural product allicin and a newly isolated bacteriophage, named BD523, was constructed herein. This combination significantly lowered effective dosage of allicin and effectually overcame bacterial drug-resistance. We experimentally evidenced that allicin interacts with bacterial DNA in the groove region by inserting itself into the DNA double helix and, subsequently, disrupts the bacterial DNA by cleaving phosphate diester bonds of deoxynucleotides. Further, BD523 destroys the cell wall and membrane of bacteria by synthesizing lyase proteins, including holin and endolysins. Thus, the synergistic effect of the combination benefits from complementary targeting mechanisms of allicin and BD523. They cooperatively act on bacterial DNA, cell wall, and membrane to improve antibacterial efficiency and avoid drug-resistance. IMPORTANCE Bacterial drug-resistance is a serious problem afflicting pharmacologists all over the world. Many strategies have been developed and practiced to overcome it, but almost no one is satisfactory due to the continual change of bacteria. Combinations of antibiotics and bacteriophages are promising because of the cooperation of 2 bacterial killers with distinct mechanisms. The combination of allicin and an Enterobacter cloacae bacteriophage reported herein can significantly improve the effect of allicin against E. cloacae. Its synergistic effect was even superior to the combination of bacteriophage and neomycin, of which the MIC was significantly lower than allicin. It was ascribed to the complementary antibacterial and the possible resistance-proof mechanism of bacteriophage and allicin. This study provided a pragmatic way to conquer the cunning bacterium, and may offer reference for research and development of new bacterial killers.