Antibacterial Activity and Pharmacokinetic Profile of a Promising Antibacterial Agent: 22-(2-Amino-phenylsulfanyl)-22-Deoxypleuromutilin

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.

Discovery of Novel Pleuromutilin Derivatives as Potent Antibacterial Agents for the Treatment of MRSA Infection

“…Following exposure to 2× MIC and 4× MIC for 2 h, the PAE of compound 9 was 1.54 and 1.71 h. These results indicated that compound 9 displayed a concentration-independent PAE and possessed a similar PAE as tiamulin (2× MIC for 1.65 h and 4× MIC for 2.04 h) [27]. Thus, the results of the PAE might guide us in the rational use of compound 9 in future clinical practice and the evaluation of adverse reactions of antibiotics and combined use [25]. The results are presented in terms of the log 10 CFU/mL change.…”

“…As an important, well-established pharmacodynamic parameter, post-antibiotic effect (PAE) refers to a period of time after the antibiotic has been completely removed from the culture medium with continual inhibition of bacterial growth [25]. A long PAE antibiotic might have a favorable outcome in clinical use, such as the ability to have to a lessfrequent interval of administration, potentially reduced treatment cost and inhibition of the development of drug resistance [26].…”

Anti-inflammatory activity of lefamulin versus azithromycin and dexamethasone in vivo and in vitro in a lipopolysaccharide-induced lung neutrophilia mouse model

“…Valnemulin treatment in murine RAW 264.7 macrophages also significantly inhibited LPS-induced production of inflammatory mediators, including nitric oxide, prostaglandin E 2 , TNF-α, and IL-6 [ 37 ]. Likewise, significantly reduced TNF-α, IL-6, and CCL-2 serum levels were observed in a methicillin-resistant Staphylococcus aureus wound infection mouse model following treatment with amphenmulin, a pleuromutilin derivative currently in development for veterinary use [ 38 ]; due to the model used, however, further studies are needed to determine if these effects were the direct result of anti-inflammatory activity, an indirect consequence of antimicrobial activity, or both.…”

A click chemistry approach to pleuromutilin derivatives, evaluation of anti-MRSA activity and elucidation of binding mode by surface plasmon resonance and molecular docking

“…Methicillin-resistant Staphylococcus aureus (MRSA) is a bacterium with a broad spectrum of drug resistance 1 , 2 . The prevalence of MRSA infection had become a serious medical problem in hospital and community settings 3 .…”