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. 2021 Jun 8;26(12):3502.
doi: 10.3390/molecules26123502.

Antibacterial Activity of a Promising Antibacterial Agent: 22-(4-(2-(4-Nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin

Xiang-Yi Zuo  1 , Hong Gao  1 , Mei-Ling Gao  1 , Zhen Jin  1 , You-Zhi Tang  1   2
Affiliations

Antibacterial Activity of a Promising Antibacterial Agent: 22-(4-(2-(4-Nitrophenyl-piperazin-1-yl)-acetyl)-piperazin-1-yl)-22-deoxypleuromutilin

Xiang-Yi Zuo et al. Molecules. .

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.

Keywords: LC-MS/MS; MRSA; antibacterial activity; pharmacokinetic; pleuromutilin derivative.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Structure of pleuromutilin, lefamulin, ATTM, tiamulin, and NPDM.
Figure 2
Figure 2
Time–kill curves for MRSA ATCC 43300 and S. aureus ATCC 29213 with different concentrations of NPDM and tiamulin: (A) NPDM against MRSA; (B) NPDM against S. aureus; (C) tiamulin against MRSA; (D) tiamulin against S. aureus.
Figure 3
Figure 3
The bacterial growth kinetic curves for MRSA ATCC 43300 exposed to NPDM for 1 h (A) or 2 h (B) and tiamulin for 1 h (C) or 2 h (D).
Figure 4
Figure 4
Cytotoxicity of NPDM and tiamulin using BRL-3A cells tested using the MTT methodology.
Figure 5
Figure 5
Efficacy of tiamulin (20 mg/kg) and NPDM (20 mg/kg) against MRSA ATCC 43300 in mouse neutropenic thigh models (A). NPDM vs. growth control, ***; tiamulin vs. growth control, ***; NPDM vs. tiamulin, *. Efficacy of tiamulin (20 mg/kg) and NPDM (20 mg/kg) against S. aureus ATCC 29213 in mouse neutropenic thigh models (B). NPDM vs. growth control, ***; tiamulin vs. growth control, ***; NPDM vs. tiamulin, *. (* 0.01 < p < 0.05; *** p < 0.001).
Figure 6
Figure 6
Survival of mice challenged with MRSA ATCC 43300 after treatment with 30 mg/kg body weight of NPDM (n = 10). NPDM vs. NPDM vehicle control, ns; NPDM vs. positive control, **; NPDM vs. tiamulin, *. (ns, not significant; * 0.01 < p < 0.05; ** 0.001 < p < 0.01).
Figure 7
Figure 7
Survival of G. mellonella challenged with MRSA ATCC 43300 after treatment with different doses of NPDM (A) or tiamulin (B).
Figure 8
Figure 8
The plasma concentration–time curve of NPDM after intravenous administration.
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