Repurposing of FDA-Approved Drugs against Mycobacterium tuberculosis Target MMA4 and CmaA2

Tuberculosis (TB) is one of the most dreadful and deadliest diseases, killing millions annually. Its causative organism is a bacterium called Mycobacterium tuberculosis which primarily attacks the lungs. Tuberculosis can be classified as latent and active based on the presence/absence of the clinical manifestations. Also known as active TB, pulmonary TB is characterized by extreme infection, whereas in latent TB, no infection or symptom is seen. In this in silico study, we focus on the molecular docking-based virtual screening of 10 FDA-approved drugs which already used to treat bacterial infections against target methoxy mycolic acid synthase 4 (MMA4) and cyclopropane mycolic acid synthase (CmaA2). Drug-resistant TB is the most challenging factor for the design and formulation of anti-tuberculosis drugs. Mycolic acid plays a crucial role in the pathogenesis of TB and, therefore, can be an extremely valuable target. Based on a study conducted on mice, by rendering the hma genes (MMA4 and cmaA) inactive, no synthesis of mycolic acid is observed. The binding energy scores of each ligand docked against the target shows the affinity that happens against the Tuberculosis disease.

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REPURPOSING FDA-APPROVED DRUGS AGAINST MULTIPLE PROTEINS OF SARS-CoV-2: AN in silico STUDY

Scientific African ◽

10.1016/j.sciaf.2021.e00845 ◽

2021 ◽

pp. e00845

Author(s):

Alfred Olaoluwa Akinlalu ◽

Annapoorna Chamundi ◽

Donald Terseer Yakumbur ◽

Funmilayo I. Deborah Afolayan ◽

Ijeoma Akunna Duru ◽

...

Keyword(s):

In Silico ◽

In Silico Study ◽

Approved Drugs ◽

Fda Approved Drugs

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Development and Challenges of Antimicrobial Peptides for Therapeutic Applications

Antibiotics ◽

10.3390/antibiotics9010024 ◽

2020 ◽

Vol 9 (1) ◽

pp. 24 ◽

Cited By ~ 34

Author(s):

Charles H. Chen ◽

Timothy K. Lu

Keyword(s):

Antimicrobial Peptides ◽

Soil Bacteria ◽

Bacterial Infections ◽

Mechanisms Of Action ◽

The Body ◽

Antimicrobial Drugs ◽

Skin Secretions ◽

Approved Drugs ◽

Topical Medications ◽

Fda Approved Drugs

More than 3000 antimicrobial peptides (AMPs) have been discovered, seven of which have been approved by the U.S. Food and Drug Administration (FDA). Now commercialized, these seven peptides have mostly been utilized for topical medications, though some have been injected into the body to treat severe bacterial infections. To understand the translational potential for AMPs, we analyzed FDA-approved drugs in the FDA drug database. We examined their physicochemical properties, secondary structures, and mechanisms of action, and compared them with the peptides in the AMP database. All FDA-approved AMPs were discovered in Gram-positive soil bacteria, and 98% of known AMPs also come from natural sources (skin secretions of frogs and toxins from different species). However, AMPs can have undesirable properties as drugs, including instability and toxicity. Thus, the design and construction of effective AMPs require an understanding of the mechanisms of known peptides and their effects on the human body. This review provides an overview to guide the development of AMPs that can potentially be used as antimicrobial drugs.

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Recent Drug-Repurposing-Driven Advances in the Discovery of Novel Antibiotics

Current Medicinal Chemistry ◽

10.2174/0929867325666180706101404 ◽

2019 ◽

Vol 26 (28) ◽

pp. 5363-5388 ◽

Cited By ~ 8

Author(s):

Ananda Kumar Konreddy ◽

Grandhe Usha Rani ◽

Kyeong Lee ◽

Yongseok Choi

Keyword(s):

Drug Discovery ◽

Bacterial Infections ◽

De Novo ◽

Genetic Disorder ◽

Antibacterial Properties ◽

Drug Repurposing ◽

Global Public Health ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Novel Antibiotics

: Drug repurposing is a safe and successful pathway to speed up the novel drug discovery and development processes compared with de novo drug discovery approaches. Drug repurposing uses FDA-approved drugs and drugs that failed in clinical trials, which have detailed information on potential toxicity, formulation, and pharmacology. Technical advancements in the informatics, genomics, and biological sciences account for the major success of drug repurposing in identifying secondary indications of existing drugs. Drug repurposing is playing a vital role in filling the gap in the discovery of potential antibiotics. Bacterial infections emerged as an ever-increasing global public health threat by dint of multidrug resistance to existing drugs. This raises the urgent need of development of new antibiotics that can effectively fight multidrug-resistant bacterial infections (MDRBIs). The present review describes the key role of drug repurposing in the development of antibiotics during 2016–2017 and of the details of recently FDA-approved antibiotics, pipeline antibiotics, and antibacterial properties of various FDA-approved drugs of anti-cancer, anti-fungal, anti-hyperlipidemia, antiinflammatory, anti-malarial, anti-parasitic, anti-viral, genetic disorder, immune modulator, etc. Further, in view of combination therapies with the existing antibiotics, their potential for new implications for MDRBIs is discussed. The current review may provide essential data for the development of quick, safe, effective, and novel antibiotics for current needs and suggest acuity in its effective implications for inhibiting MDRBIs by repurposing existing drugs.

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PO 8383 THE ROLE OF PLASMA B CELLS IN MYCOBACTERIUM TUBERCULOSIS INFECTION AND DISEASE

BMJ Global Health ◽

10.1136/bmjgh-2019-edc.80 ◽

2019 ◽

Vol 4 (Suppl 3) ◽

pp. A31.2-A31

Author(s):

Awa Gindeh ◽

Simon Donkor ◽

Olumuyiwa Owolabi

Keyword(s):

Immune Response ◽

Mycobacterium Tuberculosis ◽

B Cells ◽

B Cell ◽

Bacterial Infections ◽

Relative Proportion ◽

Post Treatment ◽

Latent Tb ◽

Latent Tb Infection

BackgroundTuberculosis (TB) is still a major global health problem with about one-quarter of the global population infected with the causative pathogen, Mycobacterium tuberculosis (Mtb). The role of T-cells in the adaptive immune response against Mtb has been extensively studied with little information on the role of B-cells. B-cells produce antibodies and differentiate into plasma and memory B-cells. Plasmablasts are a subset of plasma cells only present in the peripheral circulation following an ongoing infection or vaccination. Immunoglobulin G(IgG) especially IgG2 mounts more efficient immune response against bacterial infections, mainly attributed to the high affinity of IgG2 binding to the Fcγ receptor. Therefore, we hypothesised that Mtb-specific IgG +plasmablasts may be a useful biomarker of TB infection status.MethodsEx-vivo B-cell enzyme-linked immunospot (ELISPOT) was used to identify plasmablasts responses to Mtb-specific antigens ESAT-6/CFP-10 (EC), together with non-specific Mtb purified protein derivative (PPD) and a positive (total IgG) and negative (media only) control from adults with active TB pre- and post-treatment (n=20) or with latent TB infection (LTBI; n=20) in The Gambia.ResultsFrequencies of Mtb-specific plasmablasts were significantly higher in active TB cases pre-treatment compared to post-treatment (p<0.0001) and LTBI with no difference seen following PPD stimulation. Interestingly, total IgG +cells were lower in the cases at recruitment but increased following treatment indicating the relative proportion of Mtb-specific responses were also significantly different (p=0.034) prior to therapy.ConclusionThese data show that B-cell responses are differentially modulated during active and latent TB infection, suggesting that plasmablasts may be a useful biomarker for TB infection in TB-endemic settings.

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Repurposing of existing FDA approved drugs for Neprilysin inhibition: An in-silico study

Journal of Molecular Structure ◽

10.1016/j.molstruc.2020.129073 ◽

2021 ◽

Vol 1224 ◽

pp. 129073 ◽

Cited By ~ 2

Author(s):

Runali Sankhe ◽

Ekta Rathi ◽

Suman Manandhar ◽

Avinash Kumar ◽

Sreedhara Ranganath K Pai ◽

...

Keyword(s):

In Silico ◽

In Silico Study ◽

Neprilysin Inhibition ◽

Approved Drugs ◽

Fda Approved Drugs

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Repurposing of FDA-Approved drugs to predict new inhibitors against key regulatory genes in Mycobacterium Tuberculosis

BIOCELL ◽

10.32604/biocell.2021.017019 ◽

2021 ◽

Vol 45 (6) ◽

pp. 1569-1583

Author(s):

XINJUN YANG ◽

AFTAB ALAM ◽

NAIYAR IQBAL ◽

KHALID RAZA

Keyword(s):

Mycobacterium Tuberculosis ◽

Regulatory Genes ◽

Approved Drugs ◽

Fda Approved Drugs

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Recognizing drug targets using evolutionary information: implications for repurposing FDA-approved drugs against Mycobacterium tuberculosis H37Rv

Molecular BioSystems ◽

10.1039/c5mb00476d ◽

2015 ◽

Vol 11 (12) ◽

pp. 3316-3331 ◽

Cited By ~ 11

Author(s):

Gayatri Ramakrishnan ◽

Nagasuma R. Chandra ◽

Narayanaswamy Srinivasan

Keyword(s):

Mycobacterium Tuberculosis ◽

Drug Targets ◽

Drug Repurposing ◽

Target Space ◽

Evolutionary Information ◽

Mycobacterium Tuberculosis H37rv ◽

The Past ◽

Approved Drugs ◽

Fda Approved Drugs ◽

Computational Drug Discovery

Drug repurposing to explore target space has been gaining pace over the past decade with the upsurge in the use of systematic approaches for computational drug discovery.

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Repurposing of FDA-approved drugs to target MurB and MurE enzymes in Mycobacterium tuberculosis

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1637280 ◽

2019 ◽

Vol 38 (9) ◽

pp. 2521-2532 ◽

Cited By ~ 5

Author(s):

Jyoti Rani ◽

Yumnam Silla ◽

Kasmika Borah ◽

Srinivasan Ramachandran ◽

Urmi Bajpai

Keyword(s):

Mycobacterium Tuberculosis ◽

Approved Drugs ◽

Fda Approved Drugs

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The emerging role of exosomal miRNAs as a diagnostic and therapeutic biomarker in Mycobacterium tuberculosis infection

Molecular Medicine ◽

10.1186/s10020-021-00296-1 ◽

2021 ◽

Vol 27 (1) ◽

Author(s):

Rasoul Mirzaei ◽

Sajad Babakhani ◽

Parisa Ajorloo ◽

Razieh Heidari Ahmadi ◽

Seyed Reza Hosseini-Fard ◽

...

Keyword(s):

Mycobacterium Tuberculosis ◽

Bacterial Infections ◽

Cell Types ◽

Mycobacterium Tuberculosis Infection ◽

Diagnostic Potential ◽

Exosomal Mirnas ◽

Latent Tb ◽

Latent Tb Infection ◽

Different Cell Types

AbstractTuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), has been the world’s driving fatal bacterial contagious disease globally. It continues a public health emergency, and around one-third of the global community has been affected by latent TB infection (LTBI). This is mostly due to the difficulty in diagnosing and treating patients with TB and LTBI. Exosomes are nanovesicles (40–100 nm) released from different cell types, containing proteins, lipids, mRNA, and miRNA, and they allow the transfer of one’s cargo to other cells. The functional and diagnostic potential of exosomal miRNAs has been demonstrated in bacterial infections, including TB. Besides, it has been recognized that cells infected by intracellular pathogens such as Mtb can be secreting an exosome, which is implicated in the infection’s fate. Exosomes, therefore, open a unique viewpoint on the investigative process of TB pathogenicity. This study explores the possible function of exosomal miRNAs as a diagnostic biomarker. Moreover, we include the latest data on the pathogenic and therapeutic role of exosomal miRNAs in TB.

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