Research

14 pages, 2490 KiB

Open AccessArticle

Efflux Pump (QacA, QacB, and QacC) and β-Lactamase Inhibitors? An Evaluation of 1,8-Naphthyridines against Staphylococcus aureus Strains

by Cícera Datiane de Morais Oliveira-Tintino, Saulo Relison Tintino, Ana Carolina Justino de Araújo, Cristina Rodrigues dos Santos Barbosa, Priscilla Ramos Freitas, José Bezerra de Araújo Neto, Iêda Maria Begnini, Ricardo Andrade Rebelo, Luiz Everson da Silva, Sandro Lucio Mireski, Michele Caroline Nasato, Maria Isabel Lacowicz Krautler, Humberto Medeiros Barreto, Jaime Ribeiro-Filho, Irwin Rose Alencar de Menezes and Henrique Douglas Melo Coutinho

Molecules 2023, 28(4), 1819; https://doi.org/10.3390/molecules28041819 - 15 Feb 2023

Cited by 3 | Viewed by 1897

Abstract

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of β-lactamases and efflux pumps stand out for providing a significant degree of resistance to clinically relevant antibiotics. The 1,8-naphthyridines are nitrogen heterocycles with a broad spectrum of [...] Read more.

The bacterial species Staphylococcus aureus presents a variety of resistance mechanisms, among which the expression of β-lactamases and efflux pumps stand out for providing a significant degree of resistance to clinically relevant antibiotics. The 1,8-naphthyridines are nitrogen heterocycles with a broad spectrum of biological activities and, as such, are promising research targets. However, the potential roles of these compounds on bacterial resistance management remain to be better investigated. Therefore, the present study evaluated the antibacterial activity of 1,8-naphthyridine sulfonamides, addressing their ability to act as inhibitors of β-lactamases and efflux pump (QacA/B and QacC) against the strains SA-K4414 and SA-K4100 of S. aureus. All substances were prepared at an initial concentration of 1024 μg/mL, and their minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. Subsequently, their effects on β-lactamase- and efflux pump-mediated antibiotic resistance was evaluated from the reduction of the MIC of ethidium bromide (EtBr) and β-lactam antibiotics, respectively. The 1,8-naphthyridines did not present direct antibacterial activity against the strains SA-K4414 and SA-K4100 of S. aureus. On the other hand, when associated with antibiotics against both strains, the compounds reduced the MIC of EtBr and β-lactam antibiotics, suggesting that they may act by inhibiting β-lactamases and efflux pumps such as QacC and QacA/B. However, further research is required to elucidate the molecular mechanisms underlying these observed effects. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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11 pages, 1942 KiB

Open AccessArticle

Oxymatrine Alleviates Gentamicin-Induced Renal Injury in Rats

by Songyao Kang, Tingting Chen, Zhihui Hao, Xiao Yang, Mingfa Wang, Zhifang Zhang, Sijia Hao, Fengting Lang and Hongxia Hao

Molecules 2022, 27(19), 6209; https://doi.org/10.3390/molecules27196209 - 21 Sep 2022

Cited by 12 | Viewed by 1705

Abstract

Gentamicin is an aminoglycoside antibiotic commonly used to treat Gram-negative bacterial infections that possesses considerable nephrotoxicity. Oxymatrine is a phytochemical with the ability to counter gentamicin toxicity. We investigated the effects and protective mechanism of oxymatrine in rats. The experimental groups were as [...] Read more.

Gentamicin is an aminoglycoside antibiotic commonly used to treat Gram-negative bacterial infections that possesses considerable nephrotoxicity. Oxymatrine is a phytochemical with the ability to counter gentamicin toxicity. We investigated the effects and protective mechanism of oxymatrine in rats. The experimental groups were as follows: Control, Oxymatrine only group (100 mg/kg/d), Gentamicin only group (100 mg/kg/d), Gentamicin (100 mg/kg/d) plus Oxymatrine (100 mg/kg/d) group (n = 10). All rats were treated for seven continuous days. The results indicated that oxymatrine alleviated gentamicin-induced kidney injury, and decreased rats’ kidney indices and NAG (N-acetyl-beta-d-glucosaminidase), BUN (blood urea nitrogen) and CRE (creatine) serum levels. The oxymatrine-treated group sustained less histological damage. Oxymatrine also relived gentamicin-induced oxidative and nitrative stress, indicated by the increased SOD (superoxidase dismutase), GSH (glutathione) and CAT (catalase) activities and decreased MDA (malondialdehyde), iNOS (inducible nitric oxide synthase) and NO (nitric oxide) levels. Caspase-9 and -3 activities were also decreased in the oxymatrine-treated group. Oxymatrine exhibited a potent anti-inflammatory effect on gentamicin-induced kidney injury, down-regulated the Bcl-2ax and NF-κB mRNAs, and upregulated Bcl-2, HO-1 and Nrf2 mRNAs in the kidney tissue. Our investigation revealed the renal protective effect of oxymatrine in gentamicin-induced kidney injury for the first time. The effect was achieved through activation of the Nrf2/HO-1 pathways. The study underlines the potential clinical application of oxymatrine as a renal protectant agent for gentamicin therapy. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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14 pages, 3509 KiB

Open AccessArticle

Notch3-Mediated mTOR Signaling Pathway Is Involved in High Glucose-Induced Autophagy in Bovine Kidney Epithelial Cells

by Yaocheng Cui, Jing Fang, Hongrui Guo, Hengmin Cui, Junliang Deng, Shumin Yu, Liping Gou, Fengyuan Wang, Xiaoping Ma, Zhihua Ren, Yue Xie, Yi Geng, Ya Wang and Zhicai Zuo

Molecules 2022, 27(10), 3121; https://doi.org/10.3390/molecules27103121 - 13 May 2022

Cited by 2 | Viewed by 1531

Abstract

It is reported that Notch3 and mTOR signaling pathways are involved in autophagy, and both can be activated by high glucose (HG). However, the relationship between Notch3 and mTOR and how Notch3 affects mTOR to regulate HG-induced autophagy in bovine kidney epithelial cells [...] Read more.

It is reported that Notch3 and mTOR signaling pathways are involved in autophagy, and both can be activated by high glucose (HG). However, the relationship between Notch3 and mTOR and how Notch3 affects mTOR to regulate HG-induced autophagy in bovine kidney epithelial cells is still unclear. The purpose of this study is to explore how Notch3 affects mTOR to modulate HG-induced autophagy in bovine kidney cells. Our results showed that HG treatment significantly decreased the cell viability of MDBK cells in a dose-dependent manner. HG treatment significantly increased the expression of LC3-II/I ratio and Beclin1 protein and significantly decreased the expression of p62 protein. Consistently, LC3 fluorescence signal formation was detected by immunofluorescence in both dose and time-dependent manners. In addition, HG treatment significantly increased the expression of Notch3 protein and decreased the expression of the p-mTOR protein in both dose and time-dependent manners. Inhibition of Notch3 upregulated the expression of p-mTOR and p62 protein, and downregulated the expression of LC3-II/I ratio and Beclin1 protein. Besides, the function of Notch3 was investigated. In this study, inhibition of Notch3 activity significantly increased the viability of HG-stimulated MDBK cells. In summary, our results revealed that the Notch3-mediated mTOR signaling pathway was involved in HG-induced autophagy in MDBK cells. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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11 pages, 5190 KiB

Open AccessArticle

Poloxamer 407/188 Binary Thermosensitive Gel as a Moxidectin Delivery System: In Vitro Release and In Vivo Evaluation

by Xiangchun Ruan, Jidong Hu, Lianshou Lu, Youwei Wang, Chunlian Tang, Faquan Liu, Xiuge Gao, Li Zhang, Hao Wu, Xianhui Huang and Qing Wei

Molecules 2022, 27(10), 3063; https://doi.org/10.3390/molecules27103063 - 10 May 2022

Cited by 8 | Viewed by 1657

Abstract

Moxidectin (MXD) is an antiparasitic drug used extensively in veterinary clinics. In this study, to develop a new formulation of MXD, a thermosensitive gel of MXD (MXD-TG) was prepared based on poloxamer 407/188. Furthermore, the gelation temperature, the stability, in vitro release kinetics [...] Read more.

Moxidectin (MXD) is an antiparasitic drug used extensively in veterinary clinics. In this study, to develop a new formulation of MXD, a thermosensitive gel of MXD (MXD-TG) was prepared based on poloxamer 407/188. Furthermore, the gelation temperature, the stability, in vitro release kinetics and in vivo pharmacokinetics of MXD-TG were evaluated. The results showed that the gelation temperature was approximately 27 °C. MXD-TG was physically stable and can be released continuously for more than 96 h in vitro. The Korsmeyer–Peppas model provided the best fit to the release kinetics, and the release mechanism followed a diffusive erosion style. MXD-TG was released persistently for over 70 days in sheep. Part of pharmacokinetic parameters had a difference in female and male sheep (p < 0.05). It was concluded that MXD-TG had a good stability, and its release followed the characteristics of a diffusive erosion style in vitro and a sustained release pattern in vivo. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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16 pages, 1951 KiB

Open AccessArticle

Comparative Study of Preparation, Evaluation, and Pharmacokinetics in Beagle Dogs of Curcumin β-Cyclodextrin Inclusion Complex, Curcumin Solid Dispersion, and Curcumin Phospholipid Complex

by Wanrong Song, Xizhao Chen, Chongshan Dai, Degui Lin, Xuelin Pang, Di Zhang, Gang Liu, Yipeng Jin and Jiahao Lin

Molecules 2022, 27(9), 2998; https://doi.org/10.3390/molecules27092998 - 07 May 2022

Cited by 5 | Viewed by 2008

Abstract

Curcumin is a natural acidic polyphenol extracted from turmeric with a wide range of biological and pharmacological effects. However, the application of curcumin for animal production and human life is limited by a low oral bioavailability. In this study, natural curcumin was prepared [...] Read more.

Curcumin is a natural acidic polyphenol extracted from turmeric with a wide range of biological and pharmacological effects. However, the application of curcumin for animal production and human life is limited by a low oral bioavailability. In this study, natural curcumin was prepared for the curcumin β-cyclodextrin inclusion complex (CUR-β-CD), curcumin solid dispersion (CUR-PEG-6000), and curcumin phospholipid complex (CUR-HSPC) using co-precipitation, melting, and solvent methods, respectively. Curcumin complex formations were monitored using scanning electron microscopy (SEM), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) techniques via the shifts in the microscopic structure, molecular structure, and crystalline state. Subsequently, twenty-four female beagle dogs were randomly divided into four groups to receive unmodified curcumin and three other curcumin preparations. The validated UPLC–MS assay was successfully applied to pharmacokinetic and bioavailability studies of curcumin in beagle dog plasma, which were collected after dosing at 0 min (predose), 5 min, 15 min, 30 min, 40 min, 50 min, 1.5 h, 3 h, 4.5 h, 5.5 h, 6 h, 6.5 h, 9 h, and 24 h. The relative bioavailabilities of CUR-β-CD, CUR-PEG-6000, and CUR-HSPC were 231.94%, 272.37%, and 196.42%, respectively. This confirmed that CUR-β-CD, CUR-HSPC, and especially CUR-PEG-6000 could effectively improve the bioavailability of curcumin. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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13 pages, 2399 KiB

Open AccessArticle

Pogostone Enhances the Antibacterial Activity of Colistin against MCR-1-Positive Bacteria by Inhibiting the Biological Function of MCR-1

by Shengnan Xie, Li Li, Baihe Zhan, Xue Shen, Xuming Deng, Wenxi Tan and Tianqi Fang

Molecules 2022, 27(9), 2819; https://doi.org/10.3390/molecules27092819 - 28 Apr 2022

Cited by 6 | Viewed by 1676

Abstract

The emergence of the plasmid-mediated colistin resistance gene mcr-1 has resulted in the loss of available treatments for certain severe infections. Here we identified a potential inhibitor of MCR-1 for the treatment of infections caused by MCR-1-positive drug-resistant bacteria, especially MCR-1-positive carbapenem-resistant Enterobacteriaceae [...] Read more.

The emergence of the plasmid-mediated colistin resistance gene mcr-1 has resulted in the loss of available treatments for certain severe infections. Here we identified a potential inhibitor of MCR-1 for the treatment of infections caused by MCR-1-positive drug-resistant bacteria, especially MCR-1-positive carbapenem-resistant Enterobacteriaceae (CRE). A checkerboard minimum inhibitory concentration (MIC) test, a killing curve test, a growth curve test, bacterial live/dead assays, scanning electron microscope (SEM) analysis, cytotoxicity tests, molecular dynamics simulation analysis, and animal studies were used to confirm the in vivo/in vitro synergistic effects of pogostone and colistin. The results showed that pogostone could restore the bactericidal activity of colistin against all tested MCR-1-positive bacterial strains or MCR-1 mutant–positive bacterial strains (FIC < 0.5). Pogostone does not inhibit the expression of MCR-1. Rather, it inhibits the binding of MCR-1 to substrates by binding to amino acids in the active region of MCR-1, thus inhibiting the biological activity of MCR-1 and its mutants (such as MCR-3). An in vivo mouse systemic infection model, pogostone in combination with colistin resulted in 80.0% (the survival rates after monotherapy with colistin or pogostone alone were 33.3% and 40.0%) survival at 72 h after infection of MCR-1-positve Escherichia coli (E. coli) ZJ487 (blaNDM-1-carrying), and pogostone in combination with colistin led to one or more order of magnitude decreases in the bacterial burdens in the liver, spleen and kidney compared with pogostone or colistin alone. Our results confirm that pogostone is a potential inhibitor of MCR-1 for use in combination with polymyxin for the treatment of severe infections caused by MCR-1-positive Enterobacteriaceae. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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14 pages, 4287 KiB

Open AccessArticle

Synergistic Effect of Lithocholic Acid with Gentamicin against Gram-Positive Bacteria but Not against Gram-Negative Bacteria

by Hongfa Lv, Lianping Wang, Shuang Liu, Wei Hu, Jianfeng Wang, Xuming Deng and Jinying Gao

Molecules 2022, 27(7), 2318; https://doi.org/10.3390/molecules27072318 - 03 Apr 2022

Cited by 1 | Viewed by 1988

Abstract

Listeria monocytogenes (L. monocytogenes) is an important Gram-positive food-borne pathogen that severely threatens public health. A checkerboard microdilution method was performed to evaluate the synergistic effect of lithocholic acid (LCA) with Gentamicin (Genta) against L. monocytogenes. BacLight LIVE/DEAD staining, scanning [...] Read more.

Listeria monocytogenes (L. monocytogenes) is an important Gram-positive food-borne pathogen that severely threatens public health. A checkerboard microdilution method was performed to evaluate the synergistic effect of lithocholic acid (LCA) with Gentamicin (Genta) against L. monocytogenes. BacLight LIVE/DEAD staining, scanning electron microscopy and biofilm inhibition assays were further used to explore the bactericidal effect and antibiofilm effect of this combination on L. monocytogenes. Additionally, the synergistic effects of LCA derivatives with Genta were also evaluated against L. monocytogenes, S.aureus and S. suis. The results indicated that a synergistic bactericidal effect was observed for the combined therapy of LCA at the concentration without affecting bacteria viability, with Genta. Additionally, LCA in combination with Genta had a synergistic effect against Gram-positive bacteria (L. monocytogenes, S. aureus and S. suis) but not against Gram-negative bacteria (E. coli, A. baumannii and Salmonella). BacLight LIVE/DEAD staining and scanning electron microscopy analysis revealed that the combination of LCA with Genta caused L. monocytogenes membrane injury, leading to bacteria death. We found that 8 μg/mL LCA treatment effectively improved the ability of Genta to eradicate L. monocytogenes biofilms. In addition, we found that chenodeoxycholic acid, as a cholic acid derivative, also improved the bactericidal effect of Genta against Gram-positive bacteria. Our results indicate that LCA represents a broad-spectrum adjuvant with Genta for infection caused by L. monocytogenes and other Gram-positive pathogens. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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10 pages, 1069 KiB

Open AccessArticle

Polymyxin B Combined with Minocycline: A Potentially Effective Combination against bla_OXA-23-harboring CRAB in In Vitro PK/PD Model

by Xingyi Qu, Xingchen Bian, Yuancheng Chen, Jiali Hu, Xiaolan Huang, Yu Wang, Yaxin Fan, Hailan Wu, Xin Li, Yi Li, Beining Guo, Xiaofen Liu and Jing Zhang

Molecules 2022, 27(3), 1085; https://doi.org/10.3390/molecules27031085 - 06 Feb 2022

Cited by 4 | Viewed by 2395

Abstract

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing bla_OXA-23 by the checkerboard assay and in vitro dynamic [...] Read more.

Polymyxin-based combination therapy is commonly used to treat carbapenem-resistant Acinetobacter baumannii (CRAB) infections. In the present study, the bactericidal effect of polymyxin B and minocycline combination was tested in three CRAB strains containing bla_OXA-23 by the checkerboard assay and in vitro dynamic pharmacokinetics/pharmacodynamics (PK/PD) model. The combination showed synergistic or partial synergistic effect (fractional inhibitory concentration index ≤0.56) on the tested strains in checkboard assays. The antibacterial activity was enhanced in the combination group compared with either monotherapy in in vitro PK/PD model. The combination regimen (simultaneous infusion of 0.75 mg/kg polymyxin B and 100 mg minocycline via 2 h infusion) reduced bacterial colony counts by 0.9–3.5 log₁₀ colony forming units per milliliter (CFU/mL) compared with either drug alone at 24 h. In conclusion, 0.75 mg/kg polymyxin B combined with 100 mg minocycline via 2 h infusion could be a promising treatment option for CRAB bloodstream infections. Full article

(This article belongs to the Special Issue New Aspects of Pharmacology and Toxicology of Antibacterial Drugs)

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