Design, synthesis, and bioactivity of newly potent pleuromutilin derivatives

The overuse of antibiotics has led to the progressively severe issue of bacterial drug resistance. As a result, a large number of antibiotics available on the market show a notably diminished effectiveness against drug-resistant bacteria. Thus, a series of dimethylcysteamine pleuromutilin derivatives were designed and synthesized. Both in vitro and in vivo tests were conducted to evaluate their activities against bacteria. Most derivatives exhibited potent antibacterial effects against Gram - positive bacteria, and their antibacterial activities were superior to those of tiamulin. Derivative 4g showed exceptional antibacterial activity, having MIC values as low as 0.016 μg/mL. Furthermore, compared to tiamulin, it exhibited a significantly longer post-antibiotic effect (PAE) and a slower rate of resistance development. The molecular docking results of derivative 4g were excellent, and it effectively inhibited the expression of green fluorescent protein (GFP) in bacteria. Derivative 4g exhibited extremely low cytotoxicity and had low oral acute toxicity, with an LD₅₀ exceeding 2000 mg/kg of body weight. Derivative 4g demonstrated a more powerful therapeutic impact against MRSA infection compared to tiamulin and valnemulin. Considering these results, derivative 4g stands out as an extremely promising compound, having significant potential for the future development of therapeutic uses.