-
Frontiers in Immunology 2023Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses...
Immunotherapy has emerged as an effective therapeutic approach to several cancer types. The reinvigoration of tumor-infiltrating lymphocyte-mediated immune responses the blockade of immune checkpoint markers, such as program cell death-1 (PD-1) or its cognate ligand PD-L1, has been the basis for developing clinically effective anticancer therapies. We identified pentamidine, an FDA-approved antimicrobial agent, as a small-molecule antagonist of PD-L1. Pentamidine enhanced T-cell-mediated cytotoxicity against various cancer cells by increasing the secretion of IFN-γ, TNF-α, perforin, and granzyme B in the culture medium. Pentamidine promoted T-cell activation by blocking the PD-1/PD-L1 interaction. administration of pentamidine attenuated the tumor growth and prolonged the survival of tumor-bearing mice in PD-L1 humanized murine tumor cell allograft models. Histological analysis of tumor tissues showed an increased number of tumor-infiltrating lymphocytes in tissues derived from pentamidine-treated mice. In summary, our study suggests that pentamidine holds the potential to be repurposed as a novel PD-L1 antagonist that may overcome the limitations of monoclonal antibody therapy and can emerge as a small molecule cancer immunotherapy.
Topics: Mice; Animals; Pentamidine; B7-H1 Antigen; Programmed Cell Death 1 Receptor; Immunotherapy; Neoplasms
PubMed: 37205112
DOI: 10.3389/fimmu.2023.1145028 -
Cancer Science Jul 2023Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug...
Glioma-initiating cells, which comprise a heterogeneous population of glioblastomas, contribute to resistance against aggressive chemoradiotherapy. Using drug reposition, we investigated a therapeutic drug for glioma-initiating cells. Drug screening was undertaken to select candidate agents that inhibit proliferation of two different glioma-initiating cells lines. The alteration of proliferation and stemness of the two glioma-initiating cell lines, and proliferation, migration, cell cycle, and survival of these two differentiated glioma-initiating cell lines and three different glioblastoma cell lines treated with the candidate agent were evaluated. We also used a xenograft glioma mouse model to evaluate anticancer effects of treated glioma cell lines. Among the 1301 agents, pentamidine-an antibiotic for Pneumocystis jirovecii-emerged as a successful antiglioma agent. Pentamidine treatment suppressed proliferation and stemness in glioma-initiating cell lines. Proliferation and migration were inhibited in all differentiated glioma-initiating cells and glioblastoma cell lines, with cell cycle arrest and caspase-dependent apoptosis induction. The in vivo study reproduced the same findings as the in vitro studies. Pentamidine showed a stronger antiproliferative effect on glioma-initiating cells than on differentiated cells. Western blot analysis revealed pentamidine inhibited phosphorylation of signal transducer and activator of transcription 3 in all cell lines, whereas Akt expression was suppressed in glioma-initiating cells but not in differentiated lines. In the present study, we identified pentamidine as a potential therapeutic drug for glioma. Pentamidine could be promising for the treatment of glioblastomas by targeting both glioma-initiating cells and differentiated cells through its multifaceted antiglioma effects.
Topics: Humans; Mice; Animals; Glioblastoma; Pentamidine; Brain Neoplasms; Cell Proliferation; Cell Line, Tumor; Glioma; Apoptosis; Xenograft Model Antitumor Assays
PubMed: 37142416
DOI: 10.1111/cas.15827 -
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 -
Pharmaceutics Apr 2023The second-line antileishmanial compound pentamidine is administered intramuscularly or, preferably, by intravenous infusion, with its use limited by severe adverse...
The second-line antileishmanial compound pentamidine is administered intramuscularly or, preferably, by intravenous infusion, with its use limited by severe adverse effects, including diabetes, severe hypoglycemia, myocarditis and renal toxicity. We sought to test the potential of phospholipid vesicles to improve the patient compliance and efficacy of this drug for the treatment of leishmaniasis by means of aerosol therapy. The targeting to macrophages of pentamidine-loaded liposomes coated with chondroitin sulfate or heparin increased about twofold (up to ca. 90%) relative to noncoated liposomes. The encapsulation of pentamidine in liposomes ameliorated its activity on the amastigote and promastigote forms of and , and it significantly reduced cytotoxicity on human umbilical endothelial cells, for which the concentration inhibiting 50% of cell viability was 144.2 ± 12.7 µM for pentamidine-containing heparin-coated liposomes vs. 59.3 ± 4.9 µM for free pentamidine. The deposition of liposome dispersions after nebulization was evaluated with the Next Generation Impactor, which mimics human airways. Approximately 53% of total initial pentamidine in solution reached the deeper stages of the impactor, with a median aerodynamic diameter of ~2.8 µm, supporting a partial deposition on the lung alveoli. Upon loading pentamidine in phospholipid vesicles, its deposition in the deeper stages significantly increased up to ~68%, and the median aerodynamic diameter decreased to a range between 1.4 and 1.8 µm, suggesting a better aptitude to reach the deeper lung airways in higher amounts. In all, nebulization of liposome-encapsulated pentamidine improved the bioavailability of this neglected drug by a patient-friendly delivery route amenable to self-administration, paving the way for the treatment of leishmaniasis and other infections where pentamidine is active.
PubMed: 37111648
DOI: 10.3390/pharmaceutics15041163 -
Journal of Fungi (Basel, Switzerland) Mar 2023Trimethoprim-sulfamethoxazole (TMP-SMX) is a first-line pneumonia (PCP) prophylaxis agent, but monthly intravenous pentamidine (IVP) is used in immunocompromised hosts... (Review)
Review
BACKGROUND
Trimethoprim-sulfamethoxazole (TMP-SMX) is a first-line pneumonia (PCP) prophylaxis agent, but monthly intravenous pentamidine (IVP) is used in immunocompromised hosts without human immunodeficiency virus (HIV) infection because IVP is not associated with cytopenia and delayed engraftment.
METHOD
We performed a systematic review and meta-analysis to estimate breakthrough PCP incidence and adverse reactions in HIV-uninfected immunocompromised patients receiving IVP. MEDLINE, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov were searched from their inception until 15 December 2022.
RESULTS
The pooled incidence of breakthrough PCP with IVP was 0.7% (95% CI, 0.3-1.4%, 16 studies, 3025 patients) and was similar when used as first-line prophylaxis (0.5%; 95% CI, 0.2-1.4%, 7 studies, 752 patients). The pooled incidence of adverse reactions was 11.3% (95% CI, 6.7-18.6%, 14 studies, 2068 patients). The pooled adverse event-related discontinuation was 3.7% (95% CI, 1.8-7.3%, 11 studies, 1802 patients), but was lower in patients receiving IVP monthly (2.0%; 95% CI 0.7-5.7%, 7 studies, 1182 patients).
CONCLUSION
Monthly IVP is an appropriate second-line agent for PCP prophylaxis in certain non-HIV immunocompromised hosts, especially in patients with hematologic malignancies and hematopoietic stem cell transplant recipients. Using IVP for PCP prophylaxis as an alternative to oral TMP-SMX while patients are unable to tolerate enteral medication administration is feasible.
PubMed: 37108861
DOI: 10.3390/jof9040406 -
Royal Society Open Science Apr 2023Combining the hybridization and repurposing strategies, six compounds from our in-house library and having a designed hybrid structure of MBX-1162, pentamidine and...
Combining the hybridization and repurposing strategies, six compounds from our in-house library and having a designed hybrid structure of MBX-1162, pentamidine and MMV688271 were repurposed as potential antibacterial agents. Among, compounds and elicited potential sub-µg ml activity against the high-priority antibiotic-resistant Gram-positive members of ESKAPE bacteria as well as antibiotic-susceptible Gram-positive bacteria. Furthermore, they showed potential low µg ml activity against the explored critical-priority antibiotic-resistant Gram-negative members of ESKAPE bacteria. In time-kill assay, compound has effective 0.5 and 0.25 µg ml antibacterial lethal concentrations against MRSA in exponential growth phase. investigations predicted compounds and as inhibitors of the open conformation of undecaprenyl diphosphate synthase involved in bacterial isoprenoid synthesis. In addition, compounds and were predicted as inhibitors of NADPH-free but not NADPH-bound form of ketol-acid reductoisomerase and may also serve as potential B-DNA minor groove binders with possible differences in the molecular sequence recognition. Overall, compounds and are presented as multifunctional potential antibacterial agents for further development against high- and critical-priority Gram-positive and Gram-negative antibiotic-resistant ESKAPE bacterial pathogens as well as antibiotic-susceptible Gram-positive bacterial pathogens.
PubMed: 37090961
DOI: 10.1098/rsos.230020 -
Pharmaceuticals (Basel, Switzerland) Mar 2023() is a causal agent of cutaneous leishmaniasis (CL), a "", for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic...
() is a causal agent of cutaneous leishmaniasis (CL), a "", for which the search for new drugs is a priority. Benzimidazole is a scaffold used to develop antiparasitic drugs; therefore, it is interesting molecule against . In this work, a ligand-based virtual screening (LBVS) of the ZINC15 database was performed. Subsequently, molecular docking was used to predict the compounds with potential binding at the dimer interface of triosephosphate isomerase (TIM) of (TIM). Compounds were selected on binding patterns, cost, and commercial availability for in vitro assays against blood promastigotes. The compounds were analyzed by molecular dynamics simulation on TIM and its homologous human TIM. Finally, the physicochemical and pharmacokinetic properties were determined . A total of 175 molecules with docking scores between -10.8 and -9.0 Kcal/mol were obtained. Compound showed the best leishmanicidal activity (IC = 4.04 µM) with a value similar to the reference drug pentamidine (IC = 2.23 µM). Molecular dynamics analysis predicted low affinity for human TIM. Furthermore, the pharmacokinetic and toxicological properties of the compounds were suitable for developing new leishmanicidal agents.
PubMed: 36986489
DOI: 10.3390/ph16030390 -
Antibiotics (Basel, Switzerland) Mar 2023The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to... (Review)
Review
The necessity for the discovery of innovative antimicrobials to treat life-threatening diseases has increased as multidrug-resistant bacteria has spread. Due to antibiotics' availability over the counter in many nations, antibiotic resistance is linked to overuse, abuse, and misuse of these drugs. The World Health Organization (WHO) recognized 12 families of bacteria that present the greatest harm to human health, where options of antibiotic therapy are extremely limited. Therefore, this paper reviews possible new ways for the development of novel classes of antibiotics for which there is no pre-existing resistance in human bacterial pathogens. By utilizing research and technology such as nanotechnology and computational methods (such as in silico and Fragment-based drug design (FBDD)), there has been an improvement in antimicrobial actions and selectivity with target sites. Moreover, there are antibiotic alternatives, such as antimicrobial peptides, essential oils, anti-Quorum sensing agents, darobactins, vitamin B6, bacteriophages, odilorhabdins, 18β-glycyrrhetinic acid, and cannabinoids. Additionally, drug repurposing (such as with ticagrelor, mitomycin C, auranofin, pentamidine, and zidovudine) and synthesis of novel antibacterial agents (including lactones, piperidinol, sugar-based bactericides, isoxazole, carbazole, pyrimidine, and pyrazole derivatives) represent novel approaches to treating infectious diseases. Nonetheless, prodrugs (e.g., siderophores) have recently shown to be an excellent platform to design a new generation of antimicrobial agents with better efficacy against multidrug-resistant bacteria. Ultimately, to combat resistant bacteria and to stop the spread of resistant illnesses, regulations and public education regarding the use of antibiotics in hospitals and the agricultural sector should be combined with research and technological advancements.
PubMed: 36978495
DOI: 10.3390/antibiotics12030628 -
Avicenna Journal of Medicine Jan 2023pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has... (Review)
Review
pneumonia is an opportunistic fungal infection that was mainly associated with pneumonia in patients with advanced human immunodeficiency virus (HIV) disease. There has been a decline in pneumonia incidence in HIV since the introduction of antiretroviral medications. However, its incidence is increasing in non-HIV immunocompromised patients including those with solid organ transplantation, hematopoietic stem cell transplantation, solid organ tumors, autoimmune deficiencies, and primary immunodeficiency disorders. We aim to review and summarize the etiology, epidemiology, clinical presentation, diagnosis, and management of pneumonia in HIV, and non-HIV patients. HIV patients usually have mild-to-severe symptoms, while non-HIV patients present with a rapidly progressing disease. Induced sputum or bronchoalveolar lavage fluid can be used to make a definitive diagnosis of pneumonia. Trimethoprim-sulfamethoxazole is considered to be the first-line drug for treatment and has proven to be highly effective for pneumonia prophylaxis in both HIV and non-HIV patients. Pentamidine, atovaquone, clindamycin, and primaquine are used as second-line agents. While several diagnostic tests, treatments, and prophylactic regimes are available at our disposal, there is need for more research to prevent and manage this disease more effectively.
PubMed: 36969352
DOI: 10.1055/s-0043-1764375