Role of Clinical Pharmacodynamics Studies in the Era of Precision Medicines Against Cancer

Uçkun, Fatih M.; Qazi, Sanjive

doi:10.1007/978-3-319-56637-5_37-1

Cited by 2 publications

(2 citation statements)

References 88 publications

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“…Pharmacodynamics has been integral to the design of rational drug dosing regimens (Uckun and Qazi, 2019). Our findings showed that ID13 had excellent bactericidal efficiency, a long PAE, and high efficacy in a mouse thigh infection model against S. aureus CVCC 546 and was superior to DLP4 or vancomycin (Figure 7).…”

Section: Discussionmentioning

confidence: 86%

An Enhanced Variant Designed From DLP4 Cationic Peptide Against Staphylococcus aureus CVCC 546

Yang

Wang

et al. 2020

Front. Microbiol.

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Insect defensins are promising candidates for the development of potent antimicrobials against antibiotic-resistant Staphylococcus aureus (S. aureus). An insect defensin, DLP4, isolated from the hemolymph of Hermetia illucens larvae, showed low antimicrobial activity against Gram-positive (G +) pathogens and high cytotoxicity, which limited its effective therapeutic application. To obtain more potent and low cytotoxicity molecules, a series of peptides was designed based on the DLP4 template by changing the conservative site, secondary structure, charge, or hydrophobicity. Among them, a variant designated as ID13 exhibited strong antibacterial activity at low MIC values of 4-8 µg/mL to G + pathogens (S. aureus: 4 µg/mL; Staphylococcus epidermidis: 8 µg/mL; Streptococcus pneumoniae: 4 µg/mL; Streptococcus suis: 4 µg/mL), which were lower than those of DLP4 (S. aureus: 16 µg/mL; S. epidermidis: 64 µg/mL; S. pneumoniae: 32 µg/mL; S. suis: 16 µg/mL), and cytotoxicity of ID13 (71.4% viability) was less than that of DLP4 (63.8% viability). ID13 could penetrate and destroy the cell membrane of S. aureus CVCC 546, resulting in an increase in potassium ion leakage; it bound to genomic DNA (gDNA) and led to the change of gDNA conformation. After treatment with ID13, perforated, wrinkled, and collapsed S. aureus CVCC 546 cells were observed in electron microscopy. Additionally, ID13 killed over 99.99% of S. aureus within 1 h, 2 × MIC of ID13 induced a post-antibiotic effect (PAE) of 12.78 ± 0.28 h, and 10 mg/kg ID13 caused a 1.8 log 10 (CFU/g) (CFU: colony-forming units) reduction of S. aureus in infected mouse thigh muscles and a downregulation of TNF-α, IL-6, and IL-10 levels, which were superior to those of DLP4 or vancomycin. These findings indicate that ID13 may be a promising peptide antimicrobial agent for therapeutic application.

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Section: Discussionmentioning

confidence: 86%

An Enhanced Variant Designed From DLP4 Cationic Peptide Against Staphylococcus aureus CVCC 546

Yang

Wang

et al. 2020

Front. Microbiol.

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“…The combination of AMPs with antibiotics is an effective strategy to combat resistant pathogens ( Uckun and Qazi, 2019 ; Zharkova et al, 2019 ). Our results showed that the mean PAE for GUON6NH2 was 3.97 h, which was more than 2.65 times longer than that of N6NH2 (1.5 h), indicating a better bactericidal effect of GUON6NH2 against E. tarda , superior to norfloxacin ( Figures 2A,B ).…”

Section: Discussionmentioning

confidence: 99%

Marine Peptide-N6NH2 and Its Derivative-GUON6NH2 Have Potent Antimicrobial Activity Against Intracellular Edwardsiella tarda in vitro and in vivo

et al. 2021

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Edwardsiella tarda is a facultative intracellular pathogen in humans and animals. There is no effective way except vaccine candidates to eradicate intracellular E. tarda. In this study, four derivatives of marine peptide-N6NH2 were designed by an introduction of unnatural residues or substitution of natural ones, and their intracellular activities against E. tarda were evaluated in macrophages and in mice, respectively. The minimum inhibitory concentration (MIC) value of N6NH2 and GUON6NH2 against E. tarda was 8 μg/mL. GUON6NH2 showed higher stability to trypsin, lower toxicity (<1%) and longer post-antibiotic effect (PAE) than N6NH2 and other derivatives. Antibacterial mechanism results showed that GUON6NH2 could bind to LPS and destroyed outer/inner cell membranes of E. tarda, superior to N6NH2 and norfloxacin. Both N6NH2 and GUON6NH2 were internalized into macrophages mainly via lipid rafts, micropinocytosis, and microtubule polymerization, respectively, and distributed in the cytoplasm. The intracellular inhibition rate of GUON6NH2 against E. tarda was 97.05–100%, higher than that in case of N6NH2 (96.82–100%). In the E. tarda-induced peritonitis mouse model, after treatment with of 1 μmol/kg N6NH2 and GUON6NH2, intracellular bacterial numbers were reduced by 1.54- and 1.97-Log10 CFU, respectively, higher than norfloxacin (0.35-Log10 CFU). These results suggest that GUON6NH2 may be an excellent candidate for novel antimicrobial agents to treat infectious diseases caused by intracellular E. tarda.

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Role of Clinical Pharmacodynamics Studies in the Era of Precision Medicines Against Cancer

Cited by 2 publications

References 88 publications

An Enhanced Variant Designed From DLP4 Cationic Peptide Against Staphylococcus aureus CVCC 546

An Enhanced Variant Designed From DLP4 Cationic Peptide Against Staphylococcus aureus CVCC 546

Marine Peptide-N6NH2 and Its Derivative-GUON6NH2 Have Potent Antimicrobial Activity Against Intracellular Edwardsiella tarda in vitro and in vivo

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