No abstract

Serious infections caused by multidrug-resistant Staphylococcus aureus clearly urge the development of new antimicrobial agents. Drug repositioning has emerged as an alternative approach that enables us to rapidly identify effective drugs. We first reported a guanidine compound, isopropoxy benzene guanidine, had potent antibacterial activity against S. aureus. Unlike conventional antibiotics, repeated use of isopropoxy benzene guanidine had a lower probability of resistance section. We found that isopropoxy benzene guanidine triggered membrane damage by disrupting the cell membrane potential and cytoplasmic membrane integrity. Furthermore, we demonstrated that isopropoxy benzene guanidine is capable of treating invasive MRSA infections in vivo studies. These findings provided strong evidence that isopropoxy benzene guanidine represents a new chemical lead for novel antibacterial agent against multidrug-resistant S. aureus infections.

Plasmid-borne colistin resistance mediated by mcr-1 is a growing problem, which poses a serious challenge to the clinical application of colistin for Gram-negative bacterial infections. Drug combination is one of the effective strategies to treat colistin-resistant bacteria. Here, we found a guanidine compound, namely, isopropoxy benzene guanidine (IBG), which boosted the efficacy of colistin against mcr-1-positive Salmonella. This study aimed to develop a pharmacokinetics/pharmacodynamics (PK/PD) model by combining colistin with IBG against mcr-1-positive Salmonella in an intestinal infection model. Antibiotic susceptibility testing, checkerboard assays and time-kill curves were used to investigate the antibacterial activity of the synergistic activity of the combination. PK studies of colistin in the intestine were determined through oral gavage of single dose of 2, 4, 8, and 16 mg/kg of body weight in broilers with intestinal infection. On the contrary, PD studies were conducted over 24 h based on a single dose ranging from 2 to 16 mg/kg. The inhibitory effect Imax model was used for PK/PD modeling. The combination of colistin and IBG showed significant synergistic activity. The AUC0−24h/MIC index was used to evaluate the relationship between PK and PD, and the correlation was >0.9085. The AUC0−24h /MIC targets in combination required to achieve the bacteriostatic action, 3-log10 kill, and 4-log10 kill of bacterial counts were 47.55, 865.87, and 1894.39, respectively. These results can facilitate the evaluation of the use of IBG as a potential colistin adjuvant in the treatment of intestinal diseases in broilers caused by colistin-resistant Salmonella.

This study aimed to evaluate the antibacterial activity of isopropoxy benzene guanidine (IBG) against C. perfringens based on pharmacokinetics/pharmacodynamics (PK/PD) modeling in broilers. The PK parameters of IBG in the plasma and ileal content of C. perfringens-infected broilers following oral administration at 2, 30, and 60 mg/kg body weight were investigated. in vivo PD studies were conducted over oral administration ranging from 2 to 60 mg/kg and repeated every 12 h for 3 days. The inhibitory Imax model was used for PK/PD modeling. Results showed that the MIC of IBG against C. perfringens was 0.5–32 mg/L. After oral administration of IBG, the peak concentration (Cmax), maximum concentration time (Tmax), and area under the concentration-time curve (AUC) in ileal content of broilers were 10.97–1,036.64 mg/L, 2.39–4.27 h, and 38.31–4,266.77 mg·h/L, respectively. After integrating the PK and PD data, the AUC0 − 24h/MIC ratios needed for the bacteriostasis, bactericidal activity, and bacterial eradication were 4.00, 240.74, and 476.98 h, respectively. For dosage calculation, a dosage regimen of 12.98 mg/kg repeated every 12 h for 3 days was be therapeutically effective in broilers against C. perfringens with MIC ≤ 2 mg/L. In addition, IBG showed potent activity against C. perfringens, which may be responsible for cell membrane destruction. These results can facilitate the evaluation of the use of IBG in the treatment of intestinal diseases in broilers caused by C. perfringens.