Life Sci Space Res (Amst). 2022 Nov;35:30-35. doi: 10.1016/j.lssr.2022.07.002. Epub 2022 Jul 14.

ABSTRACT

The discovery of safe and effective radiation countermeasures (MCM) for long-duration spaceflight is challenging due to the complexity of the space radiation biology and high safety requirements. There are few if any clinically-validated molecular targets for this use case, and preclinical models have several known limitations. These challenges make the evaluation of existing FDA-approved drugs for this indication, or drug repurposing, an attractive strategy to accelerate space radiation countermeasure development. Drug repurposing offers several advantages over de novo drug discovery including established manufacturing methods, human clinical safety data, and well-understood dosing and pharmacokinetic considerations. There are limitations working with a fixed set of possible candidate compounds, but some properties of repurposed drugs can be tailored for well-defined new indications through reformulation and development of drug combinations. Drug repurposing is thus an attractive strategy for mitigating the high risks and costs of drug development and delivering new countermeasures to protect human from space radiation in long-term missions.

PMID:36336366 | DOI:10.1016/j.lssr.2022.07.002

Life Sci Space Res (Amst). 2022 Nov;35:1-3. doi: 10.1016/j.lssr.2022.10.003. Epub 2022 Oct 12.

ABSTRACT

Concerns over the health effects of space radiation exposure currently limit the duration of deep-space travel. Effective biological countermeasures could allow humanity to break this limit, facilitating human exploration and sustained presence on the Moon, Mars, or elsewhere in the Solar System. In this issue, we present a collection of 20 articles, each providing perspectives or data relevant to the implementation of a countermeasure discovery and development program. Topics include agency and drug developer perspectives, the prospects for repurposing of existing drugs or other agents, and the potential for adoption of new technologies, high-throughput screening, novel animal or microphysiological models, and alternative ground-based radiation sources. Long-term goals of a countermeasures program include reduction in the risk of radiation-exposure induced cancer death to an acceptable level and reduction in risks to the brain, cardiovascular system, and other organs.

PMID:36336355 | DOI:10.1016/j.lssr.2022.10.003

Exp Mol Med. 2022 Nov 4. doi: 10.1038/s12276-022-00873-2. Online ahead of print.

ABSTRACT

Overcoming therapeutic resistance in glioblastoma (GBM) is an essential strategy for improving cancer therapy. However, cancer cells possess various evasion mechanisms, such as metabolic reprogramming, which promote cell survival and limit therapy. The diverse metabolic fuel sources that are produced by autophagy provide tumors with metabolic plasticity and are known to induce drug or radioresistance in GBM. This study determined that autophagy, a common representative cell homeostasis mechanism, was upregulated upon treatment of GBM cells with ionizing radiation (IR). Nuclear receptor binding factor 2 (NRBF2)-a positive regulator of the autophagy initiation step-was found to be upregulated in a GBM orthotopic xenograft mouse model. Furthermore, ATP production and the oxygen consumption rate (OCR) increased upon activation of NRBF2-mediated autophagy. It was also discovered that changes in metabolic state were induced by alterations in metabolite levels caused by autophagy, thereby causing radioresistance. In addition, we found that lidoflazine-a vasodilator agent discovered through drug repositioning-significantly suppressed IR-induced migration, invasion, and proliferation by inhibiting NRBF2, resulting in a reduction in autophagic flux in both in vitro models and in vivo orthotopic xenograft mouse models. In summary, we propose that the upregulation of NRBF2 levels reprograms the metabolic state of GBM cells by activating autophagy, thus establishing NRBF2 as a potential therapeutic target for regulating radioresistance of GBM during radiotherapy.

PMID:36333468 | DOI:10.1038/s12276-022-00873-2

Eur J Med Chem. 2022 Oct 25;244:114867. doi: 10.1016/j.ejmech.2022.114867. Online ahead of print.

ABSTRACT

The Hedgehog signaling pathway plays a vital role in embryonic development and tissue patterning. Aberrant regulation of this pathway is commonly associated with the occurrence, development and progression of various types of malignancies. The development of inhibitors targeting Hedgehog pathway has attracted significant interests in cancer therapy and led to the discovery of three drugs Vismodegib, Sonidegib and Glasdegib. However, their clinical application has been hampered due to adverse effects and resistance issues, highlighting the urgent need for new inhibitors. Herein we give a systematic overview of the current status and characteristics of various approaches to developing the Hedgehog pathway inhibitors, including library screening, natural product-oriented approach, analogue approach, drug repositioning, in silico tools and others. The future prospects are also discussed for the discovery and development of next-generation inhibitors.

PMID:36332550 | DOI:10.1016/j.ejmech.2022.114867

Mol Divers. 2022 Nov 4. doi: 10.1007/s11030-022-10550-1. Online ahead of print.

ABSTRACT

The World Health Organization (WHO) recently declared the monkeypox outbreak 'A public health emergency of international concern'. The monkeypox virus belongs to the same Orthopoxvirus genus as smallpox. Although smallpox drugs are recommended for use against monkeypox, monkeypox-specific drugs are not yet available. Drug repurposing is a viable and efficient approach in the face of such an outbreak. Therefore, we present a computational drug repurposing study to identify the existing approved drugs which can be potential inhibitors of vital monkeypox virus proteins, thymidylate kinase and D9 decapping enzyme. The target protein structures of the monkeypox virus were modelled using the corresponding protein structures in the vaccinia virus. We identified four potential inhibitors namely, Tipranavir, Cefiderocol, Doxorubicin, and Dolutegravir as candidates for repurposing against monkeypox virus from a library of US FDA approved antiviral and antibiotic drugs using molecular docking and molecular dynamics simulations. The main goal of this in silico study is to identify potential inhibitors against monkeypox virus proteins that can be further experimentally validated for the discovery of novel therapeutic agents against monkeypox disease.

PMID:36331784 | DOI:10.1007/s11030-022-10550-1

Curr Top Med Chem. 2022 Nov 3. doi: 10.2174/1568026623666221103091658. Online ahead of print.

ABSTRACT

The COVID-19 outbreak and the pandemic situation have hastened the research community to design a novel drug and vaccine against its causative organism, the SARS-CoV-2. The spike glycoprotein present on the surface of this pathogenic organism plays an immense role in viral entry and antigenicity. Hence, it is considered an important drug target in COVID-19 drug design. Several three-dimensional crystal structures of this SARS-CoV-2 spike protein have been identified and deposited in the Protein DataBank during the pandemic period. This accelerated the research in computer-aided drug designing, especially in the field of structure-based drug designing. This review summarizes various structure-based drug design approaches applied to this SARS-CoV-2 spike protein and its findings. Specifically, it is focused on different structure-based approaches such as molecular docking, high-throughput virtual screening, molecular dynamics simulation, drug repurposing, and target-based pharmacophore modelling and screening. These structural approaches have been applied to different ligands and datasets such as FDA-approved drugs, small molecular chemical compounds, chemical libraries, chemical databases, structural analogs, and natural compounds, which resulted in the prediction of spike inhibitors, spike-ACE-2 interface inhibitors, and allosteric inhibitors.

PMID:36330617 | DOI:10.2174/1568026623666221103091658

Brain Commun. 2022 Oct 4;4(5):fcac247. doi: 10.1093/braincomms/fcac247. eCollection 2022.

ABSTRACT

We evaluated the hypothesis that phosphodiesterase-5 inhibitors, including sildenafil and tadalafil, may be associated with reduced incidence of Alzheimer's disease and related dementia using a patient-level cohort study of Medicare claims and cell culture-based phenotypic assays. We compared incidence of Alzheimer's disease and related dementia after phosphodiesterase-5 inhibitor initiation versus endothelin receptor antagonist initiation among patients with pulmonary hypertension after controlling for 76 confounding variables through propensity score matching. Across four separate analytic approaches designed to address specific types of biases including informative censoring, reverse causality, and outcome misclassification, we observed no evidence for a reduced risk of Alzheimer's disease and related dementia with phosphodiesterase-5 inhibitors;hazard ratio (95% confidence interval): 0.99 (0.69-1.43), 1.00 (0.71-1.42), 0.67 (0.43-1.06), and 1.15 (0.57-2.34). We also did not observe evidence that sildenafil ameliorated molecular abnormalities relevant to Alzheimer's disease in most cell culture-based phenotypic assays. These results do not provide support to the hypothesis that phosphodiesterase-5 inhibitors are promising repurposing candidates for Alzheimer's disease and related dementia.

PMID:36330433 | PMC:PMC9598543 | DOI:10.1093/braincomms/fcac247

BMC Bioinformatics. 2022 Nov 3;23(1):459. doi: 10.1186/s12859-022-04812-w.

ABSTRACT

BACKGROUND: Drug-target interactions (DTIs) prediction becomes more and more important for accelerating drug research and drug repositioning. Drug-target interaction network is a typical model for DTIs prediction. As many different types of relationships exist between drug and target, drug-target interaction network can be used for modeling drug-target interaction relationship. Recent works on drug-target interaction network are mostly concentrate on drug node or target node and neglecting the relationships between drug-target.

RESULTS: We propose a novel prediction method for modeling the relationship between drug and target independently. Firstly, we use different level relationships of drugs and targets to construct feature of drug-target interaction. Then, we use line graph to model drug-target interaction. After that, we introduce graph transformer network to predict drug-target interaction.

CONCLUSIONS: This method introduces a line graph to model the relationship between drug and target. After transforming drug-target interactions from links to nodes, a graph transformer network is used to accomplish the task of predicting drug-target interactions.

PMID:36329406 | DOI:10.1186/s12859-022-04812-w

J Mol Model. 2022 Nov 3;28(11):374. doi: 10.1007/s00894-022-05335-0.

ABSTRACT

Paracoccidioidomycosis is a systemic mycosis endemic in Latin America, and one of the etiological agents of the disease is Paracoccidioides brasiliensis. Currently, available treatments present adversities, such as duration, side effects, and drug interactions. In search of new therapy possibilities, this study evaluates drugs approved for use against the homoserine dehydrogenase enzyme, by an in silico approach, which performs an important biosynthesis phase for the fungus and is not present in the human body. The three-dimensional structure of the homoserine dehydrogenase enzyme from Paracoccidioides brasiliensis was obtained by homology modeling. The model was validated, and simulations were performed for virtual screening of molecules of drugs approved from the Drugs-libs database by the MTiOpenScreen web server. Molecular dynamics in three replicas were used for four drugs with better results, and in two more molecules as a control, the HS9 with inhibition against enzyme and HON which shows inhibition against mold structure. Based on the results of molecular dynamics and the comparison of binding free energy, the drug that obtained the best result was Bemcentinib. In comparison with the controls, it presented a highly relevant affinity with - 44.63 kcal/mol, in addition to good structural stability and occupation of the active site. Therefore, Bemcentinib is a promising molecule for the inhibition of PbHSD protein (homoserine dehydrogenase of Paracoccidioides brasiliensis) and a therapeutic option to be investigated.

PMID:36323986 | DOI:10.1007/s00894-022-05335-0

Toxicol Appl Pharmacol. 2022 Oct 31:116296. doi: 10.1016/j.taap.2022.116296. Online ahead of print.

ABSTRACT

Phthalates have been extensively used as plasticizers while manufacturing plastic-based consumer products. Estradiol mimicking properties and association studies suggest phthalates may contribute to breast cancer (BC). We performed an in-silico analysis and functional studies to understand the association between phthalate exposure and BC progression. Search for phthalate-responsive genes using the comparative toxicogenomics database identified 20 genes as commonly altered in response to multiple phthalates exposure. Of the 20 genes, 12 were significantly differentially expressed between normal and BC samples. In BC samples, 9 out of 20 genes showed a negative correlation between promoter methylation and its expression. AHR, BAX, BCL2, CAT, ESR2, IL6, and PTGS2 expression differed significantly between metastatic and non-metastatic BC samples. Gene set enrichment analysis identified metabolism, ATP-binding cassette transporters, insulin signaling, and type II diabetes as highly enriched pathways. The diagnostic assessment based on 20 genes expression suggested a sensitivity and a specificity >0.91. The aberrantly expressed phthalate interactive gene influenced the overall survival of BC patients. Drug-gene interaction analysis identified 14 genes and 523 candidate drugs, including 19 BCE treatment-approved drugs. Di(2-ethylhexyl) phthlate (DEHP) exposure increased the growth, proliferation, and migration of MCF7 and MDAMB231 cells in-vitro. DEHP exposure induced morphological changes, actin cytoskeletal remodeling, increased ROS content, reduced basal level lipid peroxidation, and induced epithelial to mesenchymal transition (EMT). The present approach can help explore the potentially damaging effects of environmental agents on cancer risk and understand the underlined pathways and molecular mechanisms.

PMID:36328110 | DOI:10.1016/j.taap.2022.116296

J Biomol Struct Dyn. 2022 Nov 3:1-14. doi: 10.1080/07391102.2022.2141889. Online ahead of print.

ABSTRACT

The discovery of a novel drug for ischemic stroke is plagued by expensive and unsuccessful outcomes. FDA-approved drugs could be a viable repurposing strategy for stroke therapy. Emerging evidence suggests the regulating role of Glutathione peroxidase (GPX4) in stroke and attracts as a potential target. To overcome limited therapeutic interventions, a drug repurposing in silico investigation of FDA-approved drugs is proposed for the GPX4 receptor in distinctive species (Homo sapiens and Mus musculus). The GPX4 UniProt wild type ids, that is, P36969 (Homo sapiens), P36970 (Rattus norvegicus) and O70325 (Mus musculus) are Swiss modelled, and resultant templates are 2OBI and 6HN3 for Homo sapiens, and 5L71 for Mus musculus with a sequence identity of ∼88%. Enrichment analysis reveals high sensitivity and ranked actives with ROC and AUC values of 0.59 and 0.61, respectively. Virtual screening at extra precision resulted hit Acarbosum, is similar between 2OBI and 6HN3, demonstrating a multiple-target specificity and Iopromide, targeting 2OBI. MD simulation at 100 ns following trajectory analysis provides RMSD (∼1.2-1.8Å), RMSF (∼1.6-2.7Å), Rgyr (∼15-15.6Å) depicting stabilisation of receptor-ligand complexes. Furthermore, average B-factor value of 2OBI, 6HN3 and 5L71 is 25Å, 24Å and 60Å with a defined resolution of 1.55Å, 1.01Å and 1.80Å, respectively, depicting the thermodynamic stability of the protein structures. The dynamic cross-correlation and principal component analysis of residual fluctuations reveal more positive correlation, high atomic displacements and greater residual clustering of residues from atomic coordinates. Therefore, Acarbosum, an FDA-approved drug, could act as a potential repurposing drug with a multi-target approach translating from preclinical to clinical stages.Communicated by Ramaswamy H. Sarma.

PMID:36326469 | DOI:10.1080/07391102.2022.2141889

Front Cell Infect Microbiol. 2022 Oct 17;12:997283. doi: 10.3389/fcimb.2022.997283. eCollection 2022.

ABSTRACT

Tuberculosis (TB) is among the most difficult infections to treat, requiring several months of multidrug therapy to produce a durable cure. The reasons necessitating long treatment times are complex and multifactorial. However, one major difficulty of treating TB is the resistance of the infecting bacterium, Mycobacterium tuberculosis (Mtb), to many distinct classes of antimicrobials. This review will focus on the major gaps in our understanding of intrinsic drug resistance in Mtb and how functional and chemical-genetics can help close those gaps. A better understanding of intrinsic drug resistance will help lay the foundation for strategies to disarm and circumvent these mechanisms to develop more potent antitubercular therapies.

PMID:36325467 | PMC:PMC9618640 | DOI:10.3389/fcimb.2022.997283

Clin Epidemiol. 2022 Oct 27;14:1217-1227. doi: 10.2147/CLEP.S381289. eCollection 2022.

ABSTRACT

INTRODUCTION: Drugs for other indications may be repurposable as disease-modifying drugs for Parkinson's disease (PD). A systematic hypothesis-free approach can enable identification of candidates for repurposing. We applied a hypothesis-free systematic approach to identify drugs associated with lower risk of PD to discover candidates with potential for repurposing as disease-modifying drugs for PD and to illustrate challenges in observational studies that simultaneously investigate multiple repurposing candidates.

METHODS: The Finnish Parkinson's disease study (FINPARK), a nationwide nested case-control study, was randomized to screening (10,183 cases, 67,849 controls) and replication (10,184 cases, 67,754 controls) samples, including cases diagnosed in 1998-2015. After screening all univariable associations of register-derived exposure to individual-drug, group- and subgroup level since 1995 (exposure ≥3 years before outcome, threshold P = 0.1), different exposure periods were used in confounder-adjusted replication analyses.

RESULTS: In screening stage, the group-level (antipsoriatics and antigout preparations) and subgroup-level (cicatrizants, topical antipsoriatics, antigout preparations and mydriatics and cycloplegics) associations were mainly due to individual drugs. Seven other drugs (eg methotrexate, drugs for chronic obstructive pulmonary disease, COPD and/or asthma) were associated with lower risk. Associations of antigout preparations and antipsoriatics were replicated. COPD/asthma drugs, methotrexate and diabetes drugs were studied in separate, indication-restricted designs.

DISCUSSION: The results reflect the known risk factors and the implied role of the immune system in PD pathogenesis and spurious associations. They underline the importance of controlling for confounding by indication, which is challenging to apply to systematic screening.

PMID:36325200 | PMC:PMC9620835 | DOI:10.2147/CLEP.S381289

Brain Commun. 2022 Oct 11;4(5):fcac260. doi: 10.1093/braincomms/fcac260. eCollection 2022.

ABSTRACT

This scientific commentary refers to 'No association between initiation of phosphodiesterase-5 inhibitors and risk of incident Alzheimer's disease and related dementia: results from the Drug Repurposing for Effective Alzheimer's Medicines (DREAM) study' by Desai et al. (https://doi.org/10.1093/braincomms/fcac247).

PMID:36324868 | PMC:PMC9598549 | DOI:10.1093/braincomms/fcac260

NPJ Precis Oncol. 2022 Nov 2;6(1):81. doi: 10.1038/s41698-022-00326-z.

ABSTRACT

Inactivating mutations of MBD4 have been reported in subsets of various tumors. A deficiency of this DNA glycosylase, recognizing specifically T:G mismatch resulting from the deamination of methyl-cytosine, results in a hypermutated phenotype due to the accumulation of CpG>TpG transitions. Here, we hypothesize that the difference in DNA metabolism consecutive to MBD4 deficiency may result in specific cytotoxicities in MBD4-deficient tumor cells in a synthetic lethality fashion. After a large-scale drug repurposing screen, we show in two isogenic MBD4 knock-out cell models that the inactivation of MBD4 sensitizes cancer cells to cytidine analogs. We further confirm the exquisite activity of gemcitabine in an MBD4-deficient co-clinical model as (i) it completely prevented the development of an MBD4-deficient uveal melanoma patient-derived xenograft and (ii) treatment in the corresponding patient resulted in an exceptional tumor response. These data suggest that patients harboring MBD4-deficient tumors may be treated efficiently by cytidine analogs.

PMID:36323843 | DOI:10.1038/s41698-022-00326-z

FEMS Microbiol Rev. 2022 Nov 2:fuac042. doi: 10.1093/femsre/fuac042. Online ahead of print.

ABSTRACT

Although COVID-19 has only recently appeared, research studies have already developed and implemented many animal models for deciphering the secrets of the disease and provided insights into the biology of SARS-CoV-2. However, there are several major factors that complicate the study of this virus in model organisms, such as the poor infectivity of clinical isolates of SARS-CoV-2 in some model species, and the absence of a persistent infection, immunopathology, severe acute respiratory distress syndrome, and none of the systemic complications which characterize COVID-19 clinically. Another important limitation is that SARS-CoV-2 mainly causes severe COVID-19 in older people with comorbidities, which represents a serious problem when attempting to use young and immunologically naïve laboratory animals in COVID-19 testing. We review here the main animal models developed so far to study COVID-19 and the unique advantages of the zebrafish model that may help to contribute to understand this disease, in particular to the identification and repurposing of drugs to treat COVID-19, to reveal the mechanism of action and side-effects of Spike-based vaccines, and to decipher the high susceptibility of aged people to COVID-19.

PMID:36323404 | DOI:10.1093/femsre/fuac042

RSC Adv. 2022 Oct 14;12(45):29525-29534. doi: 10.1039/d2ra05566j. eCollection 2022 Oct 11.

ABSTRACT

Drug-target binding affinity (DTA) prediction has drawn increasing interest due to its substantial position in the drug discovery process. The development of new drugs is costly, time-consuming, and often accompanied by safety issues. Drug repurposing can avoid the expensive and lengthy process of drug development by finding new uses for already approved drugs. Therefore, it is of great significance to develop effective computational methods to predict DTAs. The attention mechanisms allow the computational method to focus on the most relevant parts of the input and have been proven to be useful for various tasks. In this study, we proposed a novel model based on self-attention, called GSATDTA, to predict the binding affinity between drugs and targets. For the representation of drugs, we use Bi-directional Gated Recurrent Units (BiGRU) to extract the SMILES representation from SMILES sequences, and graph neural networks to extract the graph representation of the molecular graphs. Then we utilize an attention mechanism to fuse the two representations of the drug. For the target/protein, we utilized an efficient transformer to learn the representation of the protein, which can capture the long-distance relationships in the sequence of amino acids. We conduct extensive experiments to compare our model with state-of-the-art models. Experimental results show that our model outperforms the current state-of-the-art methods on two independent datasets.

PMID:36320763 | PMC:PMC9562047 | DOI:10.1039/d2ra05566j

J Pharm Investig. 2022 Oct 26:1-22. doi: 10.1007/s40005-022-00596-6. Online ahead of print.

ABSTRACT

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2, has resulted in acute respiratory distress, fatal systemic manifestations (extrapulmonary as well as pulmonary), and premature mortality among many patients. Therapy for COVID-19 has focused on the treatment of symptoms and of acute inflammation (cytokine storm) and the prevention of viral infection. Although the mechanism of COVID-19 is not fully understood, potential clinical targets have been identified for pharmacological, immunological, and vaccinal approaches.

AREA COVERED: Pharmacological approaches including drug repositioning have been a priority for initial COVID-19 therapy due to the time-consuming nature of the vaccine development process. COVID-19 drugs have been shown to manage the antiviral infection cycle (cell entry and replication of proteins and genomic RNA) and anti-inflammation. In this review, we evaluated the interaction of current COVID-19 drugs with two ATP-binding cassette transporters [P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP)] and potential drug-drug interactions (DDIs) among COVID-19 drugs, especially those associated with P-gp and BCRP efflux transporters.

EXPERT OPINION: Overall, understanding the pharmacodynamic/pharmacokinetic DDIs of COVID-19 drugs can be useful for pharmacological therapy in COVID-19 patients.

PMID:36320434 | PMC:PMC9607806 | DOI:10.1007/s40005-022-00596-6

Drug Saf. 2022 Nov 1. doi: 10.1007/s40264-022-01244-6. Online ahead of print.

ABSTRACT

INTRODUCTION: The US FDA required a Risk Evaluation and Mitigation Strategy (REMS) for phentermine/topiramate, an anti-obesity medication, to prevent congenital malformations. No REMS is required for single-ingredient topiramate, which may be used off-label for the same purpose.

OBJECTIVE: The aim of this study was to evaluate the impact of phentermine/topiramate approval in 2012 on subsequent topiramate use among patients with obesity.

METHODS: We used a national insurance claims database to conduct an interrupted time-series study (2009-2015). Enrollees aged 18-65 years in each examined calendar quarter had full insurance benefits during that quarter and the preceding 6 months. We required patients to have an obesity diagnosis and no other conditions warranting topiramate use. We calculated topiramate or comparator drug (atorvastatin, metformin) initiation rates and evaluated changes in trends before and after 2012 (transition period).

RESULTS: Among topiramate users, 80% were female, and demographic characteristics remained consistent during the study period. Between 2009 and 2011, the topiramate initiation rate (95% confidence interval) among patients with obesity was 0.85 (0.73-0.98) per 1000 patients, with no significant upward or downward trend. In the first quarter of 2013, this rate had increased more than 2.5-fold (change: + 1.36 [1.19-1.52]). Metformin and atorvastatin initiation rates did not change. Topiramate initiation rates were threefold higher than phentermine/topiramate rates during the post-approval period.

CONCLUSION: Phentermine/topiramate approval was associated with increased topiramate use among patients with obesity. Prescribers are encouraged to enhance patient education and monitoring in such clinical use since topiramate prescribing information, compared with REMS for phentermine/topiramate, has less emphasis on preventing prenatal exposure.

PMID:36318419 | DOI:10.1007/s40264-022-01244-6

Microbiol Spectr. 2022 Nov 1:e0211422. doi: 10.1128/spectrum.02114-22. Online ahead of print.

ABSTRACT

The emergence of bacterial drug resistance poses a severe threat to global public health. In particular, antimicrobial-resistant pathogens lead to a high rate of treatment failure and significantly increase mortality. Repurposing FDA-approved compounds to sensitize superbugs to conventional antibiotics provides a promising strategy to alleviate such crises. Pixantrone (PIX) has been approved for treating aggressive B-cell non-Hodgkin's lymphoma. By high-throughput drug screening, we profiled the synergistic activity between PIX and rifampin (RFP) against Gram-negative extensively drug-resistant isolates by checkerboard assay. Mechanistic studies demonstrated that PIX impacted the flagellum assembly, induced irreversible intracellular reactive oxygen species accumulation and disrupted proton motive force. In addition, the combination of PIX with RFP possesses effective antimicrobial activity against multidrug-resistant strains in vivo without detected toxicity. Collectively, these results reveal the potential of PIX in combination with RFP as a therapy option for refractory infections caused by Gram-negative pathogens. IMPORTANCE Bacterial resistance has become increasingly serious because of the widespread use and abuse of antibiotics. In particular, the emergence of multidrug-resistant bacteria has posed a serious threat to human public health. Drug repurposing, the process of finding new uses for existing drugs, provide a promising pathway to solve antimicrobial resistance. Compared to the development of novel antibiotics, this strategy leverages well-characterized pharmacology and toxicology of known drugs and is more cost-effective.

PMID:36318018 | DOI:10.1128/spectrum.02114-22