Abstract
A new pleuromutilin derivative, 22-(2-amino-phenylsulfanyl)-22-deoxypleuromutilin (amphenmulin), has been synthesized and proved excellent in vitro and in vivo efficacy than that of tiamulin against methicillin-resistant Staphylococcus aureus (MRSA), suggesting this compound may lead to a promising antibacterial agent to treat MRSA infections. In this study, the effectiveness and safety of amphenmulin were further investigated. Amphenmulin showed excellent antibacterial activity against MRSA (minimal inhibitory concentration = 0.0156~8 µg/mL) and performed time-dependent growth inhibition and a concentration-dependent postantibiotic effect (PAE). Acute oral toxicity test in mice showed that amphenmulin was a practical non-toxic drug and possessed high security as a new drug with the 50% lethal dose (LD50) above 5000 mg/kg. The pharmacokinetic properties of amphenmulin were then measured. After intravenous administration, the elimination half-life (T1/2), total body clearance (Clβ), and area under curve to infinite time (AUC0→∞) were 1.92 ± 0.28 h, 0.82 ± 0.09 L/h/kg, and 12.23 ± 1.35 μg·h/mL, respectively. After intraperitoneal administration, the T1/2, Clβ/F and AUC0→∞ were 2.64 ± 0.72 h, 4.08 ± 1.14 L/h/kg, and 2.52 ± 0.81 μg·h/mL, respectively, while for the oral route were 2.91 ± 0.81 h, 6.31 ± 2.26 L/h/kg, 1.67 ± 0.66 μg·h/mL, respectively. Furthermore, we evaluated the antimicrobial activity of amphenmulin in an experimental model of MRSA wound infection. Amphenmulin enhanced wound closure and promoted the healing of wound, which inhibited MRSA bacterial counts in the wound and decreased serum levels of the pro-inflammatory cytokines TNF-α, IL-6, and MCP-1.
Highlights
Staphylococcus aureus is a major contributor to nosocomial infections worldwide
The results of minimal inhibitory concentrations (MICs) demonstrated that amphenmulin possessed superior in vitro antibacterial The results of MIC demonstrated that amphenmulin possessed superior in vitro antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) and ATCC 29213 than tiamulin, which is consistent with our previous work [24]
It could be observed that amphenmulin showed potent activity against all Gram-positive except E. faecalis (ATCC 29212), and pretty weak activity against the Gram-negative bacteria E. coli bacteria, except E. faecalis (ATCC 29212), and pretty weak activity against the Gram-negative bacteria (ATCC 25922) and S. typhimurium (ATCC 14028)
Summary
Staphylococcus aureus is a major contributor to nosocomial infections worldwide. The pathogen is responsible for a variety of life-threatening diseases, such as sepsis, pneumonia, toxic shock syndrome, and endocarditis [1]. MRSA is S. aureus that displays resistance to methicillin and other β-lactam antibiotics, such as oxacillin, nafcillin, and carbapenems. The dissemination of MRSA represents a significant global health issue, which impacts patients in both community and health care settings [2]. The emergence of MRSA infection causes higher costs, longer hospitalization courses, and higher morbidity and mortality [3]. MRSA alone is estimated to cause about 19,000 deaths a year in the United
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