Infection and Drug Resistance (Jul 2023)
Efficacy of a Novel Antibacterial Agent Exeporfinium Chloride, (XF-73), Against Antibiotic-Resistant Bacteria in Mouse Superficial Skin Infection Models
Abstract
Chenrui Zhang,1 Jinping Li,2 Rong Lu,2 Song Wang,2 Zheng Fu,2 Zhi Yao1 1Department of Immunology, Key Laboratory of Immune Microenvironment and Disease of the Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, People’s Republic of China; 2Kangzhe Pharmaceutical Technology Development Company, Ltd., Tianjin, People’s Republic of ChinaCorrespondence: Zhi Yao, Tianjin Medical University, Tianjin, 300070, People’s Republic of China, Tel/Fax +8622-83336817, Email [email protected] Zheng Fu, Kangzhe Pharmaceutical Technology Development Company, Tianjin, 300110, People’s Republic of China, Tel/Fax +86 13821232027, Email [email protected]: The number of incidences of antimicrobial resistance is rising continually, necessitating new and effective antibacterial drugs. The present study aimed to assess the in vitro and in vivo activity of XF-73 against antibiotic-resistant Staphylococcus aureus (S. aureus) isolates and to investigate the potential mechanism of action of XF-73.Methods: The in vitro antibacterial activity of XF-73 and comparator antibacterial drugs, (mupirocin, fusidine, retapamulin, vancomycin, erythromycin, linezolid and daptomycin), against S. aureus (both antibiotic sensitive and resistant strains) was assessed using a broth microdilution method. Two different superficial Staphylococcal skin infection murine models were established to study the in vivo efficacy of XF-73 against antibiotic-resistant strains. The effect of XF-73 on the ultrastructure and cellular morphology of S. aureus was studied using transmission electron microscopy (TEM) and scanning electron microscopy (SEM).Results: The MICs (minimum inhibitory concentration) determined by the broth microdilution method for XF-73 demonstrated that the compound had a high potency against S. aureus isolates with varying susceptibility to the study drugs. Also, the antibacterial activity of XF-73 was superior or similar to most of the tested antibacterial drugs. We also found that the XF-73 dermal formulation significantly inhibited S. aureus survival in both the murine skin tape-stripping and suture superficial skin infection models, maintained a consistently high inhibitory capacity against the antibiotic-resistant strains tested and was significantly more effective than mupirocin ointment, a commonly used antibiotic for the treatment of skin infections. The morphological studies using TEM suggest that XF-73 had a rapid (2 minute) bacterial cell wall disruption activity, with longer incubation (10 minute) subsequently causing membrane damage. SEM analysis demonstrated that this cell wall and cell membrane disruption did not lead to disintegration of the plasma membrane, and did not cause bacterial cell lysis.Conclusion: Therefore, XF-73 may be an effective drug alternative to combat multi-drug-resistant skin infections in the clinical setting.Keywords: antibiotic resistance, mupirocin-resistant strains, skin infections, bacterial cell membrane, in vivo, S. aureus
