Abstract
A novel pleuromutilin derivative, 22-(4-(2-(4-nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin (NPDM), was synthesized in our laboratory and proved excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). In this study, more methods were used to further study its preliminary pharmacological effect. The antibacterial efficacy and toxicity of NPDM were evaluated using tiamulin as the reference drug. The in vitro antibacterial activity study showed that NPDM is a potent bactericidal agent against MRSA that induced time-dependent growth inhibition and a concentration-dependent post-antibiotic effect (PAE). Toxicity determination showed that the cytotoxicity of NPDM was slightly higher than that of tiamulin, but the acute oral toxicity study proved that NPDM was a low-toxic compound. In an in vivo antibacterial effect study, NPDM exhibited a better therapeutic effect than tiamulin against MRSA in a mouse thigh infection model as well as a mouse systemic infection model with neutropenia. The 50% effective dose (ED50) of NPDM in a Galleria mellonella infection model was 50.53 mg/kg. The pharmacokinetic properties of NPDM were also measured, which showed that NPDM was a rapid elimination drug in mice.
Highlights
IntroductionStaphylococcus aureus is a potentially pathogenic Gram-positive bacteria that can cause infections ranging from mild (such as skin infection) to severe (such as postsurgical wound infections and systemic infections) [1]
Staphylococcus aureus is a potentially pathogenic Gram-positive bacteria that can cause infections ranging from mild to severe [1]
For example, the in-hospital mortality rate for S. aureus bacteremia is nearly 40%, and the mortality rate of bacteremia patients caused by methicillin-resistant Staphylococcus aureus (MRSA) is 2.15 times higher than that caused by methicillinsensitive Staphylococcus aureus (MSSA) [5]
Summary
Staphylococcus aureus is a potentially pathogenic Gram-positive bacteria that can cause infections ranging from mild (such as skin infection) to severe (such as postsurgical wound infections and systemic infections) [1]. Two years after the clinical use of methicillin, Jevons isolated MRSA in 1961 [2]. MRSA is almost universal and has become one of the most common pathogens in clinics [3]. For example, the in-hospital mortality rate for S. aureus bacteremia is nearly 40%, and the mortality rate of bacteremia patients caused by MRSA is 2.15 times higher than that caused by methicillinsensitive Staphylococcus aureus (MSSA) [5]. Methicillin-resistant S. aureus is resistant to β-lactam antibiotics, and this resistance is known to be caused by the penicillinbinding protein (encoded by genes designated 2’ or 2α) on the cell wall of S. aureus, which reduces the binding affinity between MRSA and β-lactam antibiotics [2]. It is urgent and necessary to develop new antibacterial agents that have different antimicrobial mechanisms against this microorganism
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