In vitro/vivo Mechanism of Action of MP1102 With Low/Nonresistance Against Streptococcus suis Type 2 Strain CVCC 3928

Abstract

Streptococcosis is recognized as a leading infectious disease in the swine industry. <i>Streptococcus suis</i> serotype 2 is regarded as the most virulent species, which threatens human and pig health and causes serious economic losses. In this study, multiple <i>in vitro</i> and <i>in vivo</i> effects of MP1102 on multidrug resistant <i>S. suis</i> was studied for the first time. MP1102 exhibited significant antibacterial activity against <i>S. suis</i> (minimum inhibitory concentration, MIC = 0.028-0.228 μM), rapid bacteriocidal action, a longer postantibiotic effect than ceftriaxone, and a synergistic or additive effect with lincomycin, penicillin, and ceftriaxone (FICI = 0.29-0.96). No resistant mutants appeared after 30 serial passages of <i>S. suis</i> in the presence of MP1102. Flow cytometric analysis and electron microscopy observations showed that MP1102 destroyed <i>S. suis</i> cell membrane integrity and affected <i>S. suis</i> cell ultrastructure and membrane morphology. Specifically, a significantly wrinkled surface, intracellular content leakage, and cell lysis were noted, establishing a cyto-basis of nonresistance to this pathogen. DNA gel retardation and circular dichroism analysis indicated that MP1102 interacted with DNA by binding to DNA and changing the DNA conformation, even leading to the disappearance of the helical structure. This result further supported the mechanistic basis of nonresistance via interaction with an intracellular target, which could serve as a means of secondary injury after MP1102 is transported across the membrane. Upon treatment with 2.5-5.0 mg/kg MP1102, the survival of mice challenged with <i>S. suis</i> was 83.3-100%. MP1102 decreased bacterial translocation in liver, lung, spleen, and blood; inhibited the release of interleukin-1β and tumor necrosis factor-α; and relieved the lung, liver, and spleen from acute injury induced by <i>S. suis</i>. These results suggest that MP1102 is a potent novel antibacterial agent for the treatment of porcine streptococcal disease.