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. 2022 Jan 29;27(3):931.
doi: 10.3390/molecules27030931.

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

Han-Qing Fang  1 , Jie Zeng  1 , Shou-Kai Wang  1 , Xiao Wang  1 , Fang Chen  1 , Bo Li  1 , Jie Liu  1 , Zhen Jin  1   2 , Ya-Hong Liu  1   2 , You-Zhi Tang  1   2
Affiliations

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

Han-Qing Fang et al. Molecules. .

Abstract

A series of novel pleuromutilin derivatives containing nitrogen groups on the side chain of C14 were synthesized under mild conditions. Most of the synthesized derivatives displayed potent antibacterial activities. Compound 9 was found to be the most active antibacterial derivative against MRSA (MIC = 0.06 μg/mL). Furthermore, the result of time-kill curves showed that compound 9 had a certain inhibitory effect against MRSA in vitro. Moreover, according to a surface plasmon resonance (SPR) study, compound 9 (KD = 1.77 × 10-8 M) showed stronger affinity to the 50S ribosome than tiamulin (KD = 2.50 × 10-8 M). The antibacterial activity of compound 9 was further evaluated in an MRSA-infected murine thigh model. Compared to the negative control group, tiamulin reduced MRSA load (~0.7 log10 CFU/mL), and compound 9 performed a treatment effect (~1.3 log10 CFU/mL). In addition, compound 9 was evaluated in CYP450 inhibition assay and showed only moderate in vitro CYP3A4 inhibition (IC50 = 2.92 μg/mL).

Keywords: 50S ribosome; MRSA; SPR; antibacterial activity; pleuromutilin.

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Conflict of interest statement

The authors declare no conflict of interests.

Figures

Figure 1
Figure 1
Structure of pleuromutilin (1), tiamulin (2), valnemulin (3), retapamulin (4), lefamulin (5) and azamulin (6).
Scheme 1
Scheme 1
Reagent and conditions: (i) p-toluenesulfonyl chloride, ethyl acetate, NaOH, 0 °C, 3 h. (ii) a. R1R2HN, K2CO3, acetonitrile, 70 °C; b. TFA/DCM, room temperature.
Figure 2
Figure 2
(a) Time-kill curves for MRSA ATCC 43300 with different concentrations of compounds 8; (b) time-kill curves for MRSA ATCC 43300 with different concentrations of compounds 9.
Figure 2
Figure 2
(a) Time-kill curves for MRSA ATCC 43300 with different concentrations of compounds 8; (b) time-kill curves for MRSA ATCC 43300 with different concentrations of compounds 9.
Figure 3
Figure 3
The bacterial growth kinetic curves for MRSA ATCC 43300 exposed to compound 9 with concentrations of 2× MIC and 4× MIC for 2 h.
Figure 4
Figure 4
(a) The simulated docking modes of compounds 9 (green) to 1XBP; (b) the simulated docking modes of compounds 9 (green) and tiamulin (purple) to 1XBP. (Software: AutoDock Vina).
Figure 4
Figure 4
(a) The simulated docking modes of compounds 9 (green) to 1XBP; (b) the simulated docking modes of compounds 9 (green) and tiamulin (purple) to 1XBP. (Software: AutoDock Vina).
Figure 5
Figure 5
In vivo efficacy of Tiamulin (20 mg/kg) and compound 9 (20 mg/kg) in neutropenic mice thigh infection model. The mean log10 CFU is plotted of mice thigh after treatment with Tiamulin and compound 9. The **** means significant difference.
Figure 6
Figure 6
CYP3A4 inhibition by compound 9 with different concentrations.
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