Drug Dev Ind Pharm. 2021 Jul 5:1-30. doi: 10.1080/03639045.2021.1952216. Online ahead of print.

ABSTRACT

Acetylcholinesterase/Butyrylcholinesterase inhibitors are considered an effective method for treating Alzheimer's disease (AD). In this current work, we have computationally analyzed 11 new small molecule drugs used in various neurological diseases and Donepezil, a known inhibitor of acetylcholinesterase, as a positive control. We investigated these drugs for possible fundamental interactions with acetylcholinesterase and butyrylcholinesterase as both are critical in the pathophysiology of Alzheimer's disease. We have selected FDA approved compounds for repurposing as possible inhibitors of these enzymes and novel therapeutic option for Alzheimer's disease. We selected the top two molecules for each protein for their binding energies, interactions, and Donepezil, the most commonly used drug for AD treatment. Molecular simulation and dynamics studies of the top 2 drugs in each case and free energy analysis helped us reach further conclusions about the best possible drugs for repurposing. Brexipirazole and Deutetrabenazine produce encouraging results as butyrylcholinesterase and acetylcholinesterase inhibitors, respectively.

PMID:34219594 | DOI:10.1080/03639045.2021.1952216

Curr Opin Virol. 2021 Jun 19;49:183-193. doi: 10.1016/j.coviro.2021.06.004. Online ahead of print.

ABSTRACT

Near the end of 2019, a new betacoronavirus started to efficiently transmit between humans, resulting in the current COVID-19 pandemic. Unprecedented worldwide efforts were made to identify and repurpose antiviral therapeutics from collections of approved drugs and known bioactive compounds. Typical pitfalls of this approach (promiscuous/cytotoxic compounds leading to false positives), combined with bypassing antiviral drug development parameters due to urgency have resulted in often disappointing outcomes. A flood of publications, press-releases, and media posts, created confusion in the general public and sometime mobilized precious resources for clinical trials with minimal prospect of success. Breakthroughs have been made, not in the laboratory but in the clinic, resulting from the empiric identification of mitigators of clinical signs such as the discovery of improved disease management through immunomodulators. This opinion piece will aim to capture some of the lessons that we believe the COVID-19 pandemic has taught about drug repurposing screens.

PMID:34218010 | DOI:10.1016/j.coviro.2021.06.004

FEBS J. 2021 Jul 3. doi: 10.1111/febs.16106. Online ahead of print.

ABSTRACT

Alcohol consumption affects motor behavior and motor control. Both acute and chronic alcohol abuse have been extensively investigated, however the therapeutic efficacy of alcohol on some movement disorders, such as myoclonus-dystonia or essential tremor, still does not have a plausible mechanistic explanation. Yet, there are surprisingly few systematic trials with known GABAergic drugs mimicking the effect of alcohol on neurotransmission. In this brief survey, we aim to summarize the effects of ethanol (EtOH) on striatal function, providing an overview of its cellular and synaptic actions in a "circuit-centered" view. In addition, we will review both experimental and clinical evidence, in the attempt to provide a plausible mechanistic explanation for alcohol-responsive movement disorders, with particular emphasis on dystonia. Different hypotheses emerge, which may provide a rationale for the utilization of drugs that mimic alcohol effects, predicting potential drug repositioning.

PMID:34217152 | DOI:10.1111/febs.16106

Drug Discov Today. 2021 Jun 30:S1359-6446(21)00281-6. doi: 10.1016/j.drudis.2021.06.009. Online ahead of print.

ABSTRACT

The discovery and development of new medicines is expensive, time-consuming, and often inefficient, with many failures along the way. Powered by artificial intelligence (AI), language models (LMs) have changed the landscape of natural language processing (NLP), offering possibilities to transform treatment development more effectively. Here, we summarize advances in AI-powered LMs and their potential to aid drug discovery and development. We highlight opportunities for AI-powered LMs in target identification, clinical design, regulatory decision-making, and pharmacovigilance. We specifically emphasize the potential role of AI-powered LMs for developing new treatments for Coronavirus 2019 (COVID-19) strategies, including drug repurposing, which can be extrapolated to other infectious diseases that have the potential to cause pandemics. Finally, we set out the remaining challenges and propose possible solutions for improvement.

PMID:34216835 | DOI:10.1016/j.drudis.2021.06.009

Mol Divers. 2021 Jul 3. doi: 10.1007/s11030-021-10260-0. Online ahead of print.

ABSTRACT

With the advancement of combinatorial chemistry and big data, drug repositioning has boomed. In this sense, machine learning and artificial intelligence techniques offer a priori information to identify the most promising candidates. In this study, we combine QSAR and docking methodologies to identify compounds with potential inhibitory activity of vasoactive metalloproteases for the treatment of cardiovascular diseases. To develop this study, we used a database of 191 thermolysin inhibitor compounds, which is the largest as far as we know. First, we use Dragon's molecular descriptors (0-3D) to develop classification models using Bayesian networks (Naive Bayes) and artificial neural networks (Multilayer Perceptron). The obtained models are used for virtual screening of small molecules in the international DrugBank database. Second, docking experiments are carried out for all three enzymes using the Autodock Vina program, to identify possible interactions with the active site of human metalloproteases. As a result, high-performance artificial intelligence QSAR models are obtained for training and prediction sets. These allowed the identification of 18 compounds with potential inhibitory activity and an adequate oral bioavailability profile, which were evaluated using docking. Four of them showed high binding energies for the three enzymes, and we propose them as potential dual ACE/NEP inhibitors for the control of blood pressure. In summary, the in silico strategies used here constitute an important tool for the early identification of new antihypertensive drug candidates, with substantial savings in time and money.

PMID:34216326 | DOI:10.1007/s11030-021-10260-0

Chem Soc Rev. 2021 Jul 2. doi: 10.1039/d0cs01065k. Online ahead of print.

ABSTRACT

COVID-19 has resulted in huge numbers of infections and deaths worldwide and brought the most severe disruptions to societies and economies since the Great Depression. Massive experimental and computational research effort to understand and characterize the disease and rapidly develop diagnostics, vaccines, and drugs has emerged in response to this devastating pandemic and more than 130 000 COVID-19-related research papers have been published in peer-reviewed journals or deposited in preprint servers. Much of the research effort has focused on the discovery of novel drug candidates or repurposing of existing drugs against COVID-19, and many such projects have been either exclusively computational or computer-aided experimental studies. Herein, we provide an expert overview of the key computational methods and their applications for the discovery of COVID-19 small-molecule therapeutics that have been reported in the research literature. We further outline that, after the first year the COVID-19 pandemic, it appears that drug repurposing has not produced rapid and global solutions. However, several known drugs have been used in the clinic to cure COVID-19 patients, and a few repurposed drugs continue to be considered in clinical trials, along with several novel clinical candidates. We posit that truly impactful computational tools must deliver actionable, experimentally testable hypotheses enabling the discovery of novel drugs and drug combinations, and that open science and rapid sharing of research results are critical to accelerate the development of novel, much needed therapeutics for COVID-19.

PMID:34212944 | DOI:10.1039/d0cs01065k

Fundam Clin Pharmacol. 2021 Jul 1. doi: 10.1111/fcp.12712. Online ahead of print.

ABSTRACT

Glioblastoma multiforme (GBM) is known as the deadliest form of brain tumor. In addition, its high treatment resistance, heterogeneity, and invasiveness makes it one of the most challenging tumors. Depression is a common psychological disorder among patients with cancer, especially GBM. Due to the high occurrence rates of depression in GBM patients and the overlap of molecular and cellular mechanisms involved in the pathogenesis of these diseases, finding antidepressants with antitumor effects could be considered as an affordable strategy for the treatment of GBM. Antidepressants exert their antitumor properties through different mechanisms. According to available evidence in this regard, some of them can eliminate the adverse effects resulting from chemo-radiotherapy in several cancers along with their synergistic effects caused by chemotherapy. Therefore, providing comprehensive insight into this issue would guide scientists and physicians in developing further preclinical studies and clinical trials, in order to evaluate antidepressants' antitumor potential. Considering that no narrative review has been recently published on this issue, specifically on these classes of drugs, we present this article with the purpose of describing the antitumor cellular mechanisms of three classes of antidepressants as follows: tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs) in GBM.

PMID:34212424 | DOI:10.1111/fcp.12712

Bioinform Biol Insights. 2021 Jun 18;15:11779322211026728. doi: 10.1177/11779322211026728. eCollection 2021.

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as a global concern involves infections in multiple organs. Much of the research up to now has been descriptive on neurological manifestations followed by SARS-CoV-2 infection. Despite considerable efforts on effective SARS-CoV-2 vaccine, novel therapeutic options for COVID-19 comorbidities are warranted. One of the fast ways to introduce possible effective drugs for clinical trials is bioinformatics methods. We have conducted a comprehensive enrichment analysis of genes involved in SARS-CoV-2 and neurological disorders associated with COVID-19. For this purpose, gene sets were extracted from the GeneWeaver database. To find out some significant enriched findings for common genes between SARS-CoV-2 and its neurological disorders, several practical databases were used. Finally, to repurpose an efficient drug, DrugBank databases were used. Overall, we detected 139 common genes concerning SARS-CoV-2 and their neurological disorders. Interestingly, our study predicted around 6 existing drugs (ie, carvedilol, andrographolide, 2-methoxyestradiol, etanercept, polaprezinc, and arsenic trioxide) that can be used for repurposing. We found that polaprezinc (zinc l-carnosine) drug is not investigated in the context of COVID-19 till now and it could be used for the treatment of COVID-19 and its neurological manifestations. To summarize, enrichment and network data get us a coherent picture to predict drug repurposing to speed up clinical trials.

PMID:34211268 | PMC:PMC8216348 | DOI:10.1177/11779322211026728

J Clin Med. 2021 Jun 29;10(13):2881. doi: 10.3390/jcm10132881.

ABSTRACT

BACKGROUND: The Hospital-University Institute (IHU) Méditerranée Infection features a 27,000 square meter building hosting 700 employees and 75 hospitalized patients in the center of Marseille, France.

METHOD: Previous preparedness in contagious disease management allowed the IHU to manage the COVID-19 outbreak by continuing adaptation for optimal diagnosis, care and outcome. We report here the output of this management.

RESULTS: From 5 March 2020, and 26 April 2021, 608,313 PCR tests were provided for 424,919 patients and 44,089 returned positive. A total of 23,390 patients with COVID-19 were followed at IHU with an overall case fatality ratio of 1.7%. Of them 20,270 were followed as outpatients with an overall CFR of 0.17%. We performed 24,807 EKG, 5759 low dose CT Scanner, and 18,344 serology. Of the 7643 nasopharyngeal samples inoculated in cell cultures 3317 (43.3%) yielded SARS-Cov-2 isolates. Finally, 7370 SARS-Cov-2 genomes were analyzed, allowing description of the first genetic variants and their implication in the epidemiologic curves. Continuous clinical care quality evaluation provided the opportunity for 155 publications allowing a better understanding of the disease and improvement of care and 132 videos posted on the IHU Facebook network, totaling 60 million views and 390,000 followers, and dealing with COVID-19, outbreaks, epistemology, and ethics in medicine.

CONCLUSIONS: During this epidemic, IHU Méditerranée Infection played the role for which it has been created; useful clinical research to guarantee a high-quality diagnostic and care for patient and a recognized expertise.

PMID:34209634 | DOI:10.3390/jcm10132881

Molecules. 2021 Jun 30;26(13):4005. doi: 10.3390/molecules26134005.

ABSTRACT

Redox-active drugs are the mainstay of parasite chemotherapy. To assess their repurposing potential for eumycetoma, we have tested a set of nitroheterocycles and peroxides in vitro against two isolates of Madurella mycetomatis, the main causative agent of eumycetoma in Sudan. All the tested compounds were inactive except for niclosamide, which had minimal inhibitory concentrations of around 1 µg/mL. Further tests with niclosamide and niclosamide ethanolamine demonstrated in vitro activity not only against M. mycetomatis but also against Actinomadura spp., causative agents of actinomycetoma, with minimal inhibitory concentrations below 1 µg/mL. The experimental compound MMV665807, a related salicylanilide without a nitro group, was as active as niclosamide, indicating that the antimycetomal action of niclosamide is independent of its redox chemistry (which is in agreement with the complete lack of activity in all other nitroheterocyclic drugs tested). Based on these results, we propose to further evaluate the salicylanilides, niclosamidein particular, as drug repurposing candidates for mycetoma.

PMID:34209118 | DOI:10.3390/molecules26134005

Pharmaceuticals (Basel). 2021 Jun 16;14(6):573. doi: 10.3390/ph14060573.

ABSTRACT

Drug development is a complicated, slow and expensive process with high failure rates. One strategy to mitigate these factors is to recycle existing drugs with viable safety profiles and have gained Food and Drug Administration approval following extensive clinical trials. Cardiovascular and neurodegenerative diseases are difficult to treat, and there exist few effective therapeutics, necessitating the development of new, more efficacious drugs. Recent scientific studies have led to a mechanistic understanding of heart and brain disease progression, which has led researchers to assess myriad drugs for their potential as pharmacological treatments for these ailments. The focus of this review is to survey strategies for the selection of drug repurposing candidates and provide representative case studies where drug repurposing strategies were used to discover therapeutics for cardiovascular and neurodegenerative diseases, with a focus on anti-inflammatory processes where new drug alternatives are needed.

PMID:34208502 | DOI:10.3390/ph14060573

Int J Mol Sci. 2021 Jun 11;22(12):6295. doi: 10.3390/ijms22126295.

ABSTRACT

The development of DNA microarray and RNA-sequencing technology has led to an explosion in the generation of transcriptomic differential expression data under a wide range of biologic systems including those recapitulating the monogenic muscular dystrophies. Data generation has increased exponentially due in large part to new platforms, improved cost-effectiveness, and processing speed. However, reproducibility and thus reliability of data remain a central issue, particularly when resource constraints limit experiments to single replicates. This was observed firsthand in a recent rare disease drug repurposing project involving RNA-seq-based transcriptomic profiling of primary cerebrocortical cultures incubated with clinic-ready blood-brain penetrant drugs. Given the low validation rates obtained for single differential expression genes, alternative approaches to identify with greater confidence genes that were truly differentially expressed in our dataset were explored. Here we outline a method for differential expression data analysis in the context of drug repurposing for rare diseases that incorporates the statistical rigour of the multigene analysis to bring greater predictive power in assessing individual gene modulation. Ingenuity Pathway Analysis upstream regulator analysis was applied to the differentially expressed genes from the Care4Rare Neuron Drug Screen transcriptomic database to identify three distinct signaling networks each perturbed by a different drug and involving a central upstream modulating protein: levothyroxine (DIO3), hydroxyurea (FOXM1), dexamethasone (PPARD). Differential expression of upstream regulator network related genes was next assessed in in vitro and in vivo systems by qPCR, revealing 5× and 10× increases in validation rates, respectively, when compared with our previous experience with individual genes in the dataset not associated with a network. The Ingenuity Pathway Analysis based gene prioritization may increase the predictive value of drug-gene interactions, especially in the context of assessing single-gene modulation in single-replicate experiments.

PMID:34208365 | DOI:10.3390/ijms22126295

Cancers (Basel). 2021 Jun 11;13(12):2936. doi: 10.3390/cancers13122936.

ABSTRACT

Heat shock protein (Hsp) synthesis is upregulated in a wide range of cancers to provide the appropriate environment for tumor progression. The Hsp110 and Hsp70 families have been associated to cancer cell survival and resistance to chemotherapy. In this study, we explore the strategy of drug repurposing to find new Hsp70 and Hsp110 inhibitors that display toxicity against melanoma cancer cells. We found that the hits discovered using Apg2, a human representative of the Hsp110 family, as the initial target bind also to structural regions present in members of the Hsp70 family, and therefore inhibit the remodeling activity of the Hsp70 system. One of these compounds, the spasmolytic agent pinaverium bromide used for functional gastrointestinal disorders, inhibits the intracellular chaperone activity of the Hsp70 system and elicits its cytotoxic activity specifically in two melanoma cell lines by activating apoptosis. Docking and molecular dynamics simulations indicate that this compound interacts with regions located in the nucleotide-binding domain and the linker of the chaperones, modulating their ATPase activity. Thus, repurposing of pinaverium bromide for cancer treatment appears as a promising novel therapeutic approach.

PMID:34208232 | DOI:10.3390/cancers13122936

Cancers (Basel). 2021 Jun 9;13(12):2877. doi: 10.3390/cancers13122877.

ABSTRACT

Aberrant angiogenesis is a hallmark for cancer and inflammation, a key notion in drug repurposing efforts. To delineate the anti-angiogenic properties of amifostine in a human adult angiogenesis model via 3D cell metabolomics and upon a stimulant-specific manner, a 3D cellular angiogenesis assay that recapitulates cell physiology and drug action was coupled to untargeted metabolomics by liquid chromatography-mass spectrometry and nuclear magnetic resonance spectroscopy. The early events of angiogenesis upon its most prominent stimulants (vascular endothelial growth factor-A or deferoxamine) were addressed by cell sprouting measurements. Data analyses consisted of a series of supervised and unsupervised methods as well as univariate and multivariate approaches to shed light on mechanism-specific inhibitory profiles. The 3D untargeted cell metabolomes were found to grasp the early events of angiogenesis. Evident of an initial and sharp response, the metabolites identified primarily span amino acids, sphingolipids, and nucleotides. Profiles were pathway or stimulant specific. The amifostine inhibition profile was rather similar to that of sunitinib, yet distinct, considering that the latter is a kinase inhibitor. Amifostine inhibited both. The 3D cell metabolomics shed light on the anti-angiogenic effects of amifostine against VEGF-A- and deferoxamine-induced angiogenesis. Amifostine may serve as a dual radioprotective and anti-angiogenic agent in radiotherapy patients.

PMID:34207535 | DOI:10.3390/cancers13122877

Cancers (Basel). 2021 Jun 26;13(13):3193. doi: 10.3390/cancers13133193.

ABSTRACT

The substantial costs of clinical trials, the lengthy timelines of new drug discovery and development, along the high attrition rates underscore the need for alternative strategies for finding quickly suitable therapeutics agents. Given that most approved drugs possess more than one target tightly linked to other diseases, it encourages promptly testing these drugs in patients. Over the past decades, this has led to considerable attention for drug repurposing, which relies on identifying new uses for approved or investigational drugs outside the scope of the original medical indication. The known safety of approved drugs minimizes the possibility of failure for adverse toxicology, making them attractive de-risked compounds for new applications with potentially lower overall development costs and shorter development timelines. This latter case is an exciting opportunity, specifically in oncology, due to increased resistance towards the current therapies. Indeed, a large body of evidence shows that a wealth of non-cancer drugs has beneficial effects against cancer. Interestingly, 335 drugs are currently being evaluated in different clinical trials for their potential activities against various cancers (Redo database). This review aims to provide an extensive discussion about the anti-cancer activities exerted by antimicrobial agents and presents information about their mechanism(s) of action and stage of development/evaluation.

PMID:34206772 | DOI:10.3390/cancers13133193

Viruses. 2021 Jun 22;13(7):1187. doi: 10.3390/v13071187.

ABSTRACT

Mammarenaviruses are prevalent pathogens distributed worldwide, and several strains cause severe cases of human infections with high morbidity and significant mortality. Currently, there is no FDA-approved antiviral drugs and vaccines against mammarenavirus and the potential treatment option is limited to an off-label use of ribavirin that shows only partial protective effect and associates with side effects. For the past few decades, extensive research has reported potential anti-mammarenaviral drugs and their mechanisms of action in host as well as vaccine candidates. This review describes current knowledge about mammarenavirus virology, progress of antiviral drug development, and technical strategies of drug screening.

PMID:34206216 | DOI:10.3390/v13071187

Molecules. 2021 Jun 21;26(12):3772. doi: 10.3390/molecules26123772.

ABSTRACT

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, repurposing of FDA-approved drugs such as NSAIDs against COVID-19 can provide therapeutic alternatives that could be utilized as an effective safe treatment for COVID-19. The anti-inflammatory activity of NSAIDs is also advantageous in the treatment of COVID-19, as it was found that SARS-CoV-2 is responsible for provoking inflammatory cytokine storms resulting in lung damage. In this study, 40 FDA-approved NSAIDs were evaluated through molecular docking against the main protease of SARS-CoV-2. Among the tested compounds, sulfinpyrazone 2, indomethacin 3, and auranofin 4 were proposed as potential antagonists of COVID-19 main protease. Molecular dynamics simulations were also carried out for the most promising members of the screened NSAID candidates (2, 3, and 4) to unravel the dynamic properties of NSAIDs at the target receptor. The conducted quantum mechanical study revealed that the hybrid functional B3PW91 provides a good description of the spatial parameters of auranofin 4. Interestingly, a promising structure-activity relationship (SAR) was concluded from our study that could help in the future design of potential SARS-CoV-2 main protease inhibitors with expected anti-inflammatory effects as well. NSAIDs may be used by medicinal chemists as lead compounds for the development of potent SARS-CoV-2 (Mpro) inhibitors. In addition, some NSAIDs can be selectively designated for treatment of inflammation resulting from COVID-19.

PMID:34205704 | DOI:10.3390/molecules26123772

J Pers Med. 2021 Jun 21;11(6):585. doi: 10.3390/jpm11060585.

ABSTRACT

Enhanced permeation retention (EPR) was a significant milestone discovery by Maeda et al. paving the path for the emerging field of nanomedicine to become a powerful tool in the fight against cancer. Sildenafil is a potent inhibitor of phosphodiesterase 5 (PDE-5) used for the treatment of erectile dysfunction (ED) through the relaxation of smooth muscles and the modulation of vascular endothelial permeability. Overexpression of PDE-5 has been reported in lung, colon, metastatic breast cancers, and bladder squamous carcinoma. Moreover, sildenafil has been reported to increase the sensitivity of tumor cells of different origins to the cytotoxic effect of chemotherapeutic agents with augmented apoptosis mediated through inducing the downregulation of Bcl-xL and FAP-1 expression, enhancing reactive oxygen species (ROS) generation, phosphorylating BAD and Bcl-2, upregulating caspase-3,8,9 activities, and blocking cells at G0/G1 cell cycle phase. Sildenafil has also demonstrated inhibitory effects on the efflux activity of ATP-binding cassette (ABC) transporters such as ABCC4, ABCC5, ABCB1, and ABCG2, ultimately reversing multidrug resistance. Accordingly, there has been a growing interest in using sildenafil as monotherapy or chemoadjuvant in EPR augmentation and management of different types of cancer. In this review, we critically examine the basic molecular mechanism of sildenafil related to cancer biology and discuss the overall potential of sildenafil in enhancing EPR-based anticancer drug delivery, pointing to the outcomes of the most important related preclinical and clinical studies.

PMID:34205602 | DOI:10.3390/jpm11060585

IEEE/ACM Trans Comput Biol Bioinform. 2021 Jul 1;PP. doi: 10.1109/TCBB.2021.3094217. Online ahead of print.

ABSTRACT

Predicting the interaction between a compound and a target is crucial for rapid drug repurposing. Deep learning has been successfully applied in drug-target affinity (DTA) problem. However, previous deep learning-based methods ignore modeling the direct interactions between drug and protein residues. This would lead to inaccurate learning of target representation which may change due to the drug binding effects. In addition, previous DTA methods learn protein representation solely based on a small number of protein sequences in DTA datasets while neglecting the use of proteins outside of the DTA datasets. We propose GEFA (Graph Early Fusion Affinity), a novel graph-in-graph neural network with attention mechanism to address the changes in target representation because of the binding effects. Specifically, a drug is modeled as a graph of atoms, which then serves as a node in a larger graph of residues-drug complex. The resulting model is an expressive deep nested graph neural network. We also use pre-trained protein representation powered by the recent effort of learning contextualized protein representation. The experiments are conducted under different settings to evaluate scenarios such as novel drugs or targets. The results demonstrate the effectiveness of the pre-trained protein embedding and the advantages our GEFA in modeling the nested graph for drug-target interaction.

PMID:34197324 | DOI:10.1109/TCBB.2021.3094217

ACS Infect Dis. 2021 Jul 1. doi: 10.1021/acsinfecdis.1c00195. Online ahead of print.

ABSTRACT

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a major global health concern given the increase in multiple forms of drug-resistant TB. This underscores the importance of a continuous pipeline of new anti-TB agents. Drug repurposing has shown promise in expanding the therapeutic options for TB chemotherapy. Fusidic acid (FA), a natural product-derived antibiotic, is one such candidate for repurposing. The present study aimed to understand the mechanism of action of FA and its selected analogs in M. tuberculosis. By using chemical biology and genetics, we identified elongation factor G as the target of FA in M. tuberculosis. We showed essentiality of its encoding gene fusA1 in M. tuberculosis by demonstrating that the transcriptional silencing of fusA1 is bactericidal in vitro and in macrophages. Thus, this work validated a novel drug target FusA1 in M. tuberculosis.

PMID:34196521 | DOI:10.1021/acsinfecdis.1c00195