Antibiotic resistance and drug modification: Synthesis, characterization and bioactivity of newly modified potent pleuromutilin derivatives with a substituted piperazine moiety

Antibiotic-resistant bacteria pose a major global public health concern, owing to the lack of effective antibac-terial drugs. Consequently, the discovery and development of innovative antibacterial drug classes with unique mechanisms of action are urgently needed. In this study, we designed, synthesised, and tested a series of novel pleuromutilin derivatives with piperazine linker substituted by amino acids moieties to determine their anti-bacterial properties. Most synthesized compounds exhibited potent activities against Staphylococcus aureus (S. aureus), methicillin-resistant S. aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis. Com-pound 6l, the most potent antibacterial agent created in this study, displayed a rapid bactericidal activity against MRSA, Klebsiella pneumoniae and S. aureus cfr N12. Moreover, pharmacokinetics study of compound 6l exhibited good PK performance with a low in vivo clearance (CL = 1965 mL/h/kg) and a suitable half-life (T1/2 = 11.614 +/- 5.123 h). Molecular docking experiments revealed the binding model of compound 6l to the unmethylated A2503 of peptidyl transferase centre of 23S rRNA. Interaction pattern of 6l with cfr-mediated ribosomes revealed by molecular dynamics. Moreover in vivo mouse systemic infection experiments with compound 6l revealed its effectiveness against MRSA and S. aureus cfr N12 with the ED50 of 11.08 mg/kg and 14.63 mg/kg body weight, respectively.

Automated summary

In this study, novel pleuromutilin derivatives with piperazine linker substituted by amino acids moieties were designed, synthesized, and tested for their antibacterial properties. Compound 6l showed the most potent antibacterial activity against MRSA, Klebsiella pneumoniae, and S. aureus cfr N12. The pharmacokinetics study of compound 6l demonstrated good PK performance with low clearance and suitable half-life. Molecular docking experiments revealed the binding model of compound 6l to the peptidyl transferase center of 23S rRNA, and in vivo mouse infection experiments showed its effectiveness against MRSA and S. aureus cfr N12.