INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Zhixin Lei,Longfukang Yao,Yuqing Tan,Zhiqun Lei,Taolei Sun
The overexpression of virulence factors and the induced inflammatory cytokine storm, resulting in tissue damage, represent significant challenges in treating antibiotic-resistant bacterial infections with conventional antibiotics. Herein, we have developed a bifunctional nanoparticle loaded with antibiotics (PSA@PLGA-TD/SMT) designed for precise response to the virulence proteins of drug-resistant bacteria while protecting the host from excessive inflammatory damage. This is achieved by modifying polylactic- co -glycolic acid (PLGA) nanoparticles with polysialic acid (PSA). Tildipirosin (TD), through hydrophobic interactions, is encapsulated within the core, while S-Methylisothiourea (SMT) is electrostatically adsorbed onto the shell layer. In vitro, the polysialic acid in the nanoparticles interacts with the neuraminidase overexpressed on the surface of Glaesserella parasuis (Gps), triggering disintegration and subsequent release of TD, which effectively kills the bacteria. Additionally, SMT functions to suppress the secretion of inducible nitric oxide synthase (NOS2), promoting the phenotypic transformation of macrophages and reducing the expression of pro-inflammatory factors. Ultimately, PSA@PLGA-TD/SMT achieves an extended drug circulation time through its prolonged retention effect, effectively alleviating discomfort caused by resistant bacteria. Therefore, the construction of nanocarriers for precise targeting of drug-resistant pathogens, delivering antibiotics, and preventing host-induced inflammatory damage presents an effective treatment strategy. This approach not only addresses the direct issue of bacterial eradication but also mitigates the collateral damage typically associated with severe infections, offering a more comprehensive and nuanced approach to managing drug-resistant bacterial infections.
研究领域:
生物医学工程
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微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Microbiology
·
2018
·
IF 4.019
Zeng Dongping,Sun Meizhen,Lin Zhoumeng,Li Miao,Gehring Ronette,Zeng Zhenling
Tildipirosin, a 16-membered-ring macrolide antimicrobial, has recently been approved for the treatment of swine respiratory disease and bovine respiratory disease. This macrolide is extensively distributed to the site of respiratory infection followed by slow elimination. Clinical efficacy has been demonstrated in cattle and swine clinical field trials. However, the pharmacokinetic/pharmacodynamic (PK/PD) index that best correlates with the efficacy of tildipirosin remains undefined. The objective of this study was to develop a PK/PD model following subcutaneous injection of tildipirosin against Pasteurella multocida in a murine lung infection model. The PK studies of unbound (f) tildipirosin in plasma were determined following subcutaneous injection of single doses of 1, 2, 4, 6, and 8 mg/kg of body weight in neutropenic lung-infected mice. The PD studies were conducted over 24 h based on twenty intermittent dosing regimens, of which total daily dose ranged from 1 to 32 mg/kg and dosage intervals included 6, 8, 12, and 24 h. The minimum inhibitory concentration (MIC) of tildipirosin against P. multocida was determined in serum. The inhibitory effect Imax model was employed for PK/PD modeling. The area under the unbound concentration-time profile over 24 h to MIC (fAUC0-24 h/MIC) was the PK/PD index that best described the antibacterial activity in the murine infection model. The fAUC0-24 h/MIC targets required to achieve the bacteriostatic action, a 1-log10 kill and 2-log10 kill of bacterial counts were 19.93, 31.89, and 53.27 h, respectively. These results can facilitate efforts to define more rational designs of dosage regimens of tildipirosin using classical PK/PD concepts for the treatment of respiratory diseases in pigs and cattle.
研究领域:
兽医学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Biomaterials Science
·
2025
·Vol. 13
·期 5
·1272-1285
·
IF 5.7
Zhixin Lei,Xiaoli Cai,Juan Wan,Ze Li,Taolei Sun
To enhance the antibacterial efficacy of tildipirosin against Staphylococcus aureus (S.A.) infections, optimized solid lipid nanoparticles loaded with tildipirosin (SLN-TD) were developed, using docosanoic acid (DA), octadecanoic acid (OA), hexadecanoic acid (HA), and tetradecanoic acid (TA) as lipid components. The efficacy of these nanoparticles against S.A. was evaluated using orthogonal design analysis. FTIR, DLS, HPLC, and TEM analyses confirmed that tildipirosin was successfully incorporated into the solid lipid nanoparticles, resulting in an optimal nanoparticle drug delivery system with a particle size of 322.63 ± 1.51 nm, a zeta potential of 37.83 ± 0.95 mV, an encapsulation efficiency of 82.23 ± 0.45%, and a drug loading capacity of 7.36 ± 0.18%. The SLN-TD system exhibited high stability, effective sustained release in vitro, and enhanced intracellular activity against S.A. Pharmacokinetic studies in rats administered 4 mg kg−1via intramuscular and oral routes showed that, compared to unencapsulated tildipirosin (TD), SLN-TD provided sustained release in vivo and improved gastrointestinal absorption with higher bioavailability. Additionally, in a mouse model of S.A. infection, SLN-TD demonstrated superior antibacterial activity and sustained drug delivery for effective treatment. This study offers a promising multifunctional nanoparticle drug delivery system for the effective treatment of S.A. infections and enhances the oral bioavailability of tildipirosin, with potential applications in veterinary medicine.
研究领域:
药剂学
·
微生物学
·
兽医学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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