In vitro and in vivo antibacterial activity, resistance analysis and molecular docking study of pleuromutilin
Sujuan Wu1,2,3, Lu Zhang1,2,3, Xinyue Luo1,2,3
1Guangdong Provincial Key Laboratory of Veterinary Pharmaceutics Development and Safety Evaluation, College of Veterinary Medicine, South China Agricultural University, Guangzhou 510642, P.R.China.
Objectives:
To evaluate the in vitro and in vivo antimicrobial activity of pleuromutilin derivatives modified with C14 side-chain against Streptococcus suis.
Methods:
To determine the minimum inhibitory concentrations (MICs) of 268 pleuromutilin derivatives with C14 side-chain modifications against S. suis ATCC 43 765 using the broth dilution method. Derivative B43, B49, B52, B53 and B54, which exhibited better antimicrobial activity, were selected for further investigation of their in vitro antibacterial effect, cytotoxicity, and in vivo antibacterial effect.
Results:
Determination activity of five derivatives against clinical strains (n = 37), as well as growth and time-killing curves. Those experiments showed that all the five derivatives had good activity against S. suis in vitro. Resistance-inducing assays demonstrated that, except for B43, the derivatives had similar abilities to induce resistance to tiamulin. In addition, the five derivatives did not have erythrocyte haemolytic toxicity (0.25-16 mg/L) and cytotoxicity (1.25-80 mg/L). In the mouse thigh infection model, the derivative of B49 exhibited superior antibacterial efficacy. About 40 mg/kg B49 had good activity and improved the survival rate of mice by 33.3% in the S. suis mouse peritonitis model. Molecular docking study and scanning electron microscopy revealed that B49 can effectively bind to the active site of the 50S ribosome and disrupt cell membranes.
Conclusions:
A total of 68.66% of the 268 C14 side-chain modified pleuromutilin derivatives showed potent activity against S. suis. Among them, B49 showed good in vitro and in vivo antimicrobial effects against S. suis, indicating that B49 can be intensively studied as an antimicrobial candidate compound.
Insights
New pleuromutilin derivatives show potent antimicrobial activity against Streptococcus suis. Derivative B49 demonstrated significant in vitro and in vivo efficacy, suggesting its potential as a novel antimicrobial candidate.
Area of Science:
- Medicinal Chemistry
- Microbiology
- Pharmacology
Background:
- Streptococcus suis is a significant pathogen causing severe infections in both animals and humans.
- Pleuromutilin derivatives represent a promising class of antibiotics with a unique mechanism of action.
- Modifications of the C14 side chain of pleuromutilins aim to enhance antimicrobial potency and spectrum.
Purpose of the Study:
- To evaluate the antimicrobial activity of novel C14 side-chain modified pleuromutilin derivatives against Streptococcus suis.
- To assess the in vitro and in vivo efficacy and safety profiles of selected potent derivatives.
- To elucidate the mechanism of action of the most promising derivative.
Main Methods:
- Broth microdilution method was used to determine the minimum inhibitory concentrations (MICs) of 268 pleuromutilin derivatives against S. suis.
- In vitro antibacterial effects, cytotoxicity, and resistance induction potential were evaluated for lead compounds.
- In vivo efficacy was assessed using mouse thigh and peritonitis infection models.
Main Results:
- 68.66% of the tested pleuromutilin derivatives exhibited potent activity against S. suis.
- Derivative B49 demonstrated superior in vitro and in vivo antibacterial efficacy with no observed erythrocyte haemolytic toxicity or cytotoxicity.
- B49 treatment improved survival rates in mouse models and was shown to disrupt bacterial cell membranes by binding to the 50S ribosome.
Conclusions:
- C14 side-chain modification of pleuromutilins yields compounds with significant antimicrobial activity against S. suis.
- Derivative B49 is a highly promising candidate for further development as a novel antimicrobial agent.
- The findings support the continued investigation of pleuromutilin derivatives for combating S. suis infections.
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