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Frontiers in Veterinary Science 2022African trypanosomiasis is associated with , and pathogens in African animal trypanosomiasis (AAT) while and are responsible for chronic and acute human African... (Review)
Review
African trypanosomiasis is associated with , and pathogens in African animal trypanosomiasis (AAT) while and are responsible for chronic and acute human African trypanosomiasis (HAT), respectively. Suramin sodium suppresses ATP generation during the glycolytic pathway and is ineffective against and infections. Resistance to suramin is associated with pathogen altered transport proteins. Melarsoprol binds irreversibly with pyruvate kinase protein sulfhydryl groups and neutralizes enzymes which interrupts the trypanosome ATP generation. Melarsoprol resistance is associated with the adenine-adenosine transporter, P2, due to point mutations within this transporter. Eflornithine is used in combination with nifurtimox. Resistance to eflornithine is caused by the deletion or mutation of TbAAT6 gene which encodes the transmembrane amino acid transporter that delivers eflornithine into the cell, thus loss of transporter protein results in eflornithine resistance. Nifurtimox alone is regarded as a poor trypanocide, however, it is effective in melarsoprol-resistant gHAT patients. Resistance is associated with loss of a single copy of the genes encoding for nitroreductase enzymes. Fexinidazole is recommended for first-stage and non-severe second-stage illnesses in gHAT and resistance is associated with trypanosome bacterial nitroreductases which reduce fexinidazole. In AAT, quinapyramine sulfate interferes with DNA synthesis and suppression of cytoplasmic ribosomal activity in the mitochondria. Quinapyramine sulfate resistance is due to variations in the potential of the parasite's mitochondrial membrane. Pentamidines create cross-links between two adenines at 4-5 pairs apart in adenine-thymine-rich portions of DNA. It also suppresses type II topoisomerase in the mitochondria of parasites. Pentamidine resistance is due to loss of mitochondria transport proteins P2 and HAPT1. Diamidines are most effective against group and act the P2/TbAT1 transporters. Diminazene aceturate resistance is due to mutations that alter the activity of P2, TeDR40 (). Isometamidium chloride is primarily employed in the early stages of trypanosomiasis and resistance is associated with diminazene resistance. Phenanthridine (homidium bromide, also known as ethidium bromide) acts by a breakdown of the kinetoplast network and homidium resistance is comparable to isometamidium. In humans, the development of resistance and adverse side effects against monotherapies has led to the adoption of nifurtimox-eflornithine combination therapy. Current efforts to develop new prodrug combinations of nifurtimox and eflornithine and nitroimidazole fexinidazole as well as benzoxaborole SCYX-7158 (AN5568) for HAT are in progress while little comparable progress has been done for the development of novel therapies to address trypanocide resistance in AAT.
PubMed: 35356785
DOI: 10.3389/fvets.2022.828111 -
Biomolecules Apr 2021S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may...
S100P, a small calcium-binding protein, associates with the p53 protein with micromolar affinity. It has been hypothesized that the oncogenic function of S100P may involve binding-induced inactivation of p53. We used H-N HSQC experiments and molecular modeling to study the molecular interactions between S100P and p53 in the presence and absence of pentamidine. Our experimental analysis indicates that the S100P-53 complex formation is successfully disrupted by pentamidine, since S100P shares the same binding site for p53 and pentamidine. In addition, we showed that pentamidine treatment of ZR-75-1 breast cancer cells resulted in reduced proliferation and increased p53 and p21 protein levels, indicating that pentamidine is an effective antagonist that interferes with the S100P-p53 interaction, leading to re-activation of the p53-21 pathway and inhibition of cancer cell proliferation. Collectively, our findings suggest that blocking the association between S100P and p53 by pentamidine will prevent cancer progression and, therefore, provide a new avenue for cancer therapy by targeting the S100P-p53 interaction.
Topics: Binding Sites; Calcium-Binding Proteins; Cell Line, Tumor; Cell Proliferation; Humans; Models, Molecular; Neoplasm Proteins; Pentamidine; Protein Binding; Protein Domains; Protein Interaction Mapping; S100 Proteins; Tumor Suppressor Protein p53
PubMed: 33923162
DOI: 10.3390/biom11050634 -
Pathogens (Basel, Switzerland) Sep 2022Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of... (Review)
Review
Background Human African trypanocide resistance (HATr) is a challenge for the eradication of Human African Trypansomiaisis (HAT) following the widespread emergence of increased monotherapy drug treatment failures against Trypanosoma brucei gambiense and T. b. rhodesiense that are associated with changes in pathogen receptors. Methods: Electronic searches of 12 databases and 3 Google search websites for human African trypanocide resistance were performed using a keyword search criterion applied to both laboratory and clinical studies. Fifty-one publications were identified and included in this study using the PRISMA checklist. Data were analyzed using RevMan and random effect sizes were computed for the statistics at the 95% confidence interval. Results: Pentamidine/melarsoprol/nifurtimox cross-resistance is associated with loss of the T. brucei adenosine transporter 1/purine 2 gene (TbAT1/P2), aquaglyceroporins (TbAQP) 2 and 3, followed by the high affinity pentamidine melarsoprol transporter (HAPT) 1. In addition, the loss of the amino acid transporter (AAT) 6 is associated with eflornithine resistance. Nifurtimox/eflornithine combination therapy resistance is associated with AAT6 and nitroreductase loss, and high resistance and parasite regrowth is responsible for treatment relapse. In clinical studies, the TbAT1 proportion of total random effects was 68% (95% CI: 38.0−91.6); I2 = 96.99% (95% CI: 94.6−98.3). Treatment failure rates were highest with melarsoprol followed by eflornithine at 41.49% (95% CI: 24.94−59.09) and 6.56% (3.06−11.25) respectively. HATr-resistant phenotypes used in most laboratory experiments demonstrated significantly higher pentamidine resistance than other trypanocides. Conclusion: The emergence of drug resistance across the spectrum of trypanocidal agents that are used to treat HAT is a major threat to the global WHO target to eliminate HAT by 2030. T. brucei strains were largely resistant to diamidines and the use of high trypanocide concentrations in clinical studies have proved fatal in humans. Studies to develop novel chemotherapeutical agents and identify alternative protein targets could help to reduce the emergence and spread of HATr.
PubMed: 36297157
DOI: 10.3390/pathogens11101100 -
Microbiology Spectrum Jun 2023The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and their biofilm-relevant infections pose a threat to public health. The drug combination...
The increasing prevalence of carbapenem-resistant Enterobacteriaceae (CRE) and their biofilm-relevant infections pose a threat to public health. The drug combination strategy provides a new treatment option for CRE infections. This study explored the synergistic antibacterial, antibiofilm activities as well as the efficacy against CRE of pentamidine combined with linezolid. This study further revealed the possible mechanisms underlying the synergy of the combination. The checkerboard and time-kill assays showed that pentamidine combined with linezolid had significant synergistic antibacterial effects against CRE strains (9/10). Toxicity assays on mammal cells (mouse RAW264.7 and red blood cells) and on Galleria mellonella confirmed that the concentrations of pentamidine and/or linezolid that were used were relatively safe. Antibiofilm activity detection via crystal violet staining, viable bacteria counts, and scanning electron microscopy demonstrated that the combination enhanced the inhibition of biofilm formation and the elimination of established biofilms. The G. mellonella infection model and mouse thigh infection model demonstrated the potential efficacy of the combination. In particular, a series of mechanistic experiments elucidated the possible mechanisms for the synergy in which pentamidine disrupts the outer membranes, dissipates the membrane potentials, and devitalizes the efflux pumps of CRE, thereby facilitating the intracellular accumulation of linezolid and reactive oxygen species (ROS), which ultimately kills the bacteria. Taken together, when combined with pentamidine, which acts as an outer membrane permeabilizer and as an efflux pump inhibitor, originally ineffective linezolid becomes active in CRE and exhibits excellent synergistic antibacterial and antibiofilm effects as well as a potential therapeutic effect on CRE-relevant infections. The multidrug resistance and biofilm formation of Gram-negative bacteria (GNB) may lead to incurable "superbug" infections. Drug combinations, with the potential to augment the original treatment ranges of drugs, are alternative treatment strategies against GNB. In this study, the pentamidine-linezolid combination showed notable antibacterial and antibiofilm activity both and against the problem carbapenem-resistant Enterobacteriaceae (CRE). Pentamidine is often used as an antiprotozoal and antifungal agent, and linezolid is a defensive Gram-positive bacteria (GPB) antimicrobial. Their combination expands the treatment range to GNB. Hence, the pentamidine-linezolid pair may be an effective treatment for complex infections that are mixed by GPB, GNB, and even fungi. In terms of mechanism, pentamidine inhibited the outer membranes, membrane potentials, and efflux pumps of CRE. This might be a universal mechanism by which pentamidine, as an adjuvant, potentiates other drugs, similar to linezolid, thereby having synergistic antibacterial effects on CRE.
Topics: Mice; Animals; Linezolid; Pentamidine; Carbapenem-Resistant Enterobacteriaceae; Anti-Bacterial Agents; Drug Combinations; Microbial Sensitivity Tests; Mammals
PubMed: 37125928
DOI: 10.1128/spectrum.03138-22 -
Frontiers in Pharmacology 2022Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body...
Toll-like receptor 4 (TLR4) is a pattern-recognition receptor (PRR) that can recognize lipopolysaccharides (LPS) and initiate the immune response, to protect the body from infection. However, excessive activation of TLR4 induced by LPS leads to substantial release of pro-inflammatory factors, which may bring a cytokine storm in the body and cause severe sepsis. Existing molecules specialized in sepsis therapy are either in clinical trials or show mediocre effects. In this study, pentamidine, an approved drug used in the treatment of trypanosomiasis, was identified as a TLR4 antagonist. Saturation transferred difference (STD)-NMR spectra indicated that pentamidine directly interacted with TLR4's co-receptor myeloid differentiation protein 2 (MD2) . Cellular thermal shift assay (CETSA) showed that pentamidine binding decreased MD2 stability, which was supported by simulations that pentamidine binding rendered most regions of MD2 more flexible. Pentamidine was found to inhibit the formation of the TLR4/MD2/MyD88 complex and the activation of the TLR4 signaling axes of NF-κB and MAPKs, therefore blocking LPS-induced TLR4 signaling downstream of the pro-inflammatory factors NO, TNF-α, and IL-1β. The bioisosteric replacement of the methylene group at the center 13' site of pentamidine by the ether oxygen group significantly decreased its interactions with MD2 and abolished its TLR4 antagonist activity. Furthermore, pentamidine enhanced the survival rate of septic mice and exerted an anti-inflammatory effect on organs. All these data provide strong evidence that pentamidine may be an effective drug in alleviating inflammation and sepsis.
PubMed: 35281916
DOI: 10.3389/fphar.2022.835081 -
Acta Tropica Nov 2023Acanthamoeba keratitis (AK) is an eye disease often occurring in contact lens wearers. AK treatment is prolonged and requires multiple drugs, which can lead to adverse...
Acanthamoeba keratitis (AK) is an eye disease often occurring in contact lens wearers. AK treatment is prolonged and requires multiple drugs, which can lead to adverse effects. Our study aimed to compare the in vitro activities and safety of Miltefosine with that of conventional antimicrobial agents used to treat AK. Acanthamoeba castellanii genotype T4 was obtained from a patient with keratitis and subjected to in vitro susceptibility testing with various antimicrobial agents, including Chlorhexidine (CHX), Pentamidine isethionate (PI)Polyhexamethylene biguanide (PHMB), and Miltefosine to assess their efficacy against Acanthamoeba trophozoites and cyst. The cytotoxicity of the agents was evaluated in Vero cells, and their selectivity indexes (SI) were calculated. Chlorhexidine exhibited the highest amoebicidal activity with the highest selectivity index against the trophozoite and cyst, ranging from 1.17 to 8.35. The selectivity index of PHMB is slightly comparable to Chlorhexidine, exhibiting significant anti-Acanthamoeba activity. On the other hand, Pentamidine isethionate and Miltefosine displayed low SI among the compounds. Pentamidine isethionate was effective at high concentrations, which was toxic. Miltefosine exhibited the lowest cytotoxicity; nevertheless, due to the lowest anti-Acanthamoeba activity presented a low selectivity against the parasite. Further studies on more clinical samples and prolonged incubation time should be done to investigate the effectiveness and toxicity of drugs in both in vitro and in vivo conditions.
Topics: Chlorocebus aethiops; Animals; Humans; Acanthamoeba; Chlorhexidine; Trophozoites; Pentamidine; Vero Cells; Anti-Infective Agents; Acanthamoeba Keratitis; Cysts
PubMed: 37643658
DOI: 10.1016/j.actatropica.2023.107009 -
Drug Design, Development and Therapy 2021Pentamidine is an anti-protozoal cationic aromatic diamidine drug and has been reported to exhibit anticancer properties. We aimed to identify the effect of pentamidine...
PURPOSE
Pentamidine is an anti-protozoal cationic aromatic diamidine drug and has been reported to exhibit anticancer properties. We aimed to identify the effect of pentamidine on proliferation and migration of human ovarian cancer (OC) cell lines and the related mechanisms.
METHODS
HO8910 and Caov3 ovarian cancer cells were treated with pentamidine. MTS and colony formation assays were used to detect the proliferation ability of cells. The migration of cells was detected using wound healing and transwell assays. The protein levels of PTEN, phosphorylated Akt, Akt, N-cadherin, E-cadherin and snail were detected by Western blotting. Immunoprecipitation and Western blotting were used to detect ubiquitination levels of PTEN.
RESULTS
Our findings revealed that pentamidine inhibited both proliferation and migration of OC cells. Further investigation found that pentamidine increased the protein expression of PTEN and reduced phosphorylation levels of AKT in OC cells. Pentamidine treatment modulated PTEN stability through the ubiquitin/proteasome pathway. In addition, pentamidine inhibited the expression of N-cadherin and snail, and increased E-cadherin expression in a dose-dependent manner.
CONCLUSION
Pentamidine is involved in the maintenance of PTEN protein stability and suppresses proliferation and migration of OC cells.
Topics: Antineoplastic Agents; Antiprotozoal Agents; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dose-Response Relationship, Drug; Female; Humans; Ovarian Neoplasms; PTEN Phosphohydrolase; Pentamidine; Proto-Oncogene Proteins c-akt
PubMed: 34234416
DOI: 10.2147/DDDT.S311187 -
Journal Der Deutschen Dermatologischen... Jun 2024Mucocutaneous leishmaniasis is a severe infectious disease, predominantly endemic in Central and South America and is characterized by granulomatous, destructive mucosal... (Review)
Review
Mucocutaneous leishmaniasis is a severe infectious disease, predominantly endemic in Central and South America and is characterized by granulomatous, destructive mucosal lesions in the oral, nasal, and pharyngeal cavities. It is caused by protozoa of the genus Leishmania spp. transmitted to humans by sandflies. Mucocutaneous leishmaniasis occurs after untreated or inadequately treated cutaneous leishmaniasis and is more common in immunocompromised patients. The aim of this systematic review is to summarize all reported treatment options for mucocutaneous leishmaniasis. This review is based on all English, German, French, Spanish and Portuguese articles published in the databases "PubMed" and "Lilacs" from 1995 to 2020. Most of the medical literature is limited to case reports, small case series, retrospective studies, and a few randomized controlled trials. Various treatment options include pentavalent antimonates such as meglumine antimonate or sodium stibogluconate, amphotericin B (liposomal, deoxycholate, lipid complex, colloidal dispersion), miltefosine, and pentamidine. Other therapeutic options include itraconazole, fluconazole, ketoconazole, aminosidine sulfate, and azithromycin. The choice of drug depends primarily on its availability in the endemic area and the patient's comorbidities.
Topics: Humans; Leishmaniasis, Mucocutaneous; Antiprotozoal Agents
PubMed: 38769082
DOI: 10.1111/ddg.15424 -
The Journal of Physiology Jul 2023Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. K 11.1 (also known as hERG)...
Cardiac electrophysiology is regulated by continuous trafficking and internalization of ion channels occurring over minutes to hours. K 11.1 (also known as hERG) underlies the rapidly activating delayed-rectifier K current (I ), which plays a major role in cardiac ventricular repolarization. Experimental characterization of the distinct temporal effects of genetic and acquired modulators on channel trafficking and gating is challenging. Computer models are instrumental in elucidating these effects, but no currently available model incorporates ion-channel trafficking. Here, we present a novel computational model that reproduces the experimentally observed production, forward trafficking, internalization, recycling and degradation of K 11.1 channels, as well as their modulation by temperature, pentamidine, dofetilide and extracellular K . The acute effects of these modulators on channel gating were also incorporated and integrated with the trafficking model in the O'Hara-Rudy human ventricular cardiomyocyte model. Supraphysiological dofetilide concentrations substantially increased K 11.1 membrane levels while also producing a significant channel block. However, clinically relevant concentrations did not affect trafficking. Similarly, severe hypokalaemia reduced K 11.1 membrane levels based on long-term culture data, but had limited effect based on short-term data. By contrast, clinically relevant elevations in temperature acutely increased I due to faster kinetics, while after 24 h, I was decreased due to reduced K 11.1 membrane levels. The opposite was true for lower temperatures. Taken together, our model reveals a complex temporal regulation of cardiac electrophysiology by temperature, hypokalaemia, and dofetilide through competing effects on channel gating and trafficking, and provides a framework for future studies assessing the role of impaired trafficking in cardiac arrhythmias. KEY POINTS: K 11.1 channels underlying the rapidly activating delayed-rectifier K current are important for ventricular repolarization and are continuously shuttled from the cytoplasm to the plasma membrane and back over minutes to hours. K 11.1 gating and trafficking are modulated by temperature, drugs and extracellular K concentration but experimental characterization of their combined effects is challenging. Computer models may facilitate these analyses, but no currently available model incorporates ion-channel trafficking. We introduce a new two-state ion-channel trafficking model able to reproduce a wide range of experimental data, along with the effects of modulators of K 11.1 channel functioning and trafficking. The model reveals complex dynamic regulation of ventricular repolarization by temperature, extracellular K concentration and dofetilide through opposing acute (millisecond) effects on K 11.1 gating and long-term (hours) modulation of K 11.1 trafficking. This in silico trafficking framework provides a tool to investigate the roles of acute and long-term processes on arrhythmia promotion and maintenance.
Topics: Humans; Anti-Arrhythmia Agents; Hypokalemia; Electrophysiologic Techniques, Cardiac; Ion Channels; Arrhythmias, Cardiac; Myocytes, Cardiac; Ether-A-Go-Go Potassium Channels
PubMed: 36752166
DOI: 10.1113/JP283976 -
Beilstein Journal of Nanotechnology 2022Advanced nanoscale antimicrobials, originated from the combination of noble metal nanoparticles (NPs) with conventional antimicrobial drugs, are considered the next...
Advanced nanoscale antimicrobials, originated from the combination of noble metal nanoparticles (NPs) with conventional antimicrobial drugs, are considered the next generation of antimicrobial agents. Therefore, there is an increasing demand for rapid, eco-friendly, and relatively inexpensive synthetic approaches for the preparation of nontoxic metallic nanostructures endowed with unique physicochemical properties. Recently, we have proposed a straightforward synthetic strategy that exploits the properties of polymeric β-cyclodextrin (PolyCD) to act as both the reducing and stabilizing agent to produce monodispersed and stable gold-based NPs either as monometallic (nanoG) structures or core-shell bimetallic (nanoGS) architectures with an external silver layer. Here, we describe the preparation of a supramolecular assembly between nanoGS and pentamidine, an antileishmanial drug endowed with a wide range of therapeutic properties (i.e., antimicrobial, anti-inflammatory, and anticancer). The physicochemical characterization of the supramolecular assembly (nanoGSP) in terms of size and colloidal stability was investigated by complementary spectroscopic techniques, such as UV-vis, ζ-potential, and dynamic light scattering (DLS). Furthermore, the role of PolyCD during the reduction/stabilization of metal NPs was investigated for the first time by NMR spectroscopy.
PubMed: 36474926
DOI: 10.3762/bjnano.13.112