Effects of tafenoquine against active, dormant and resistant Mycobacterium tuberculosis

Sidrônio, Maria Gabriella S.; Branco, Ana Paula Oliveira Trigueiro Castelo; Abbadi, Bruno Lopes; Macchi, Fernanda Souza; Silveira, Maiele D.; Lock, Graziela de Araújo; Costa, Teresa Dalla; Araújo, Demétrius M. de; Cibulski, Samuel Paulo; Bizarro, Cristiano Valim; Machado, Pablo; Basso, Luiz Augusto; Rodrigues-Junior, Valnês S.

doi:10.1016/j.tube.2021.102089

Cited by 7 publications

(10 citation statements)

References 15 publications

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“…Besides our study, antimalarials, except for TAF, have demonstrated diverse antimicrobial activities. For example, artemisinin and its derivatives, mefloquine, and chloroquine have been reported to exhibit antibacterial or antifungal effects ( 19 , 42 – 44 ). A series of primaquine derivatives have been shown broad-spectrum antimicrobial activity ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

“…The exact mechanism of TAF against plasmodium is unknown, but the process may involve interference of cytochrome C reductase leading to mitochondrial membrane depolarization, as well as the production of reactive oxygen species (ROS) ( 18 ). The bioactive effects of TAF against parasites, fungi, and Mycobacterium tuberculosis have been previously reported; however, its efficacy against other bacteria is unknown ( 19 , 20 ). In the present study, using high-throughput screening, we identified TAF to be a potential antibacterial candidate against MRSA.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing of the antimalarial agent tafenoquine to combat MRSA

She,

Yang,

et al. 2023

mSystems

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Staphylococcus aureus is an important human pathogen that often leads to hospital-acquired and community-acquired infections. The appearance of methicillin-resistant S. aureus (MRSA) has made the treatment extremely challenging. There is an urgent need to develop new antimicrobial agents to combat MRSA infections. In this study, through high-throughput screening, we found that tafenoquine (TAF), an antimalarial agent, exhibited antimicrobial efficacy against MRSA and its highly resistant phenotypes of biofilm and persister cells. No resistant mutation emerged by consecutive sub-minimal inhibitory concentration of TAF induction. Mechanistic studies by fluorescent probes of SYTOX Green/DiSC3(5), molecular dynamic simulations, electron microscopy, and proteomic analysis revealed that TAF exerts antimicrobial activity mainly through selective bacterial cell membrane disruption. In addition, TAF exhibited an effective antimicrobial effect in a subcutaneous abscess model in vivo with a good toxicity profile. In conclusion, TAF may have the potential to be developed as a new antimicrobial agent to treat refractory MRSA infections. IMPORTANCE This study represents the first investigation into the antimicrobial effect of TAF against S. aureus and its potential mechanisms. Our data highlighted the effects of TAF against MRSA planktonic cells, biofilms, and persister cells, which is conducive to broadening the application of TAF. Through mechanistic studies, we revealed that TAF targets bacterial cell membranes. In addition, the in vivo experiments in mice demonstrated the safety and antimicrobial efficacy of TAF, suggesting that TAF could be a potential antibacterial drug candidate for the treatment of infections caused by multiple drug-resistant S. aureus .

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Repurposing of the antimalarial agent tafenoquine to combat MRSA

She,

Yang,

et al. 2023

mSystems

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“…All controls were performed in parallel. MBC is defined as the lowest concentration capable of causing complete inhibition of bacterial growth after 24 h at 35 °C [ 37 ]. MFC was considered to be the lowest concentration of the test product capable of inhibiting the growth of microorganisms after 24–48 h at 35 ± 2 °C/yeasts and RT (28–30 °C)/5–7 days for filamentous fungi [ 38 , 39 ].…”

Section: Methodsmentioning

confidence: 99%

Antimicrobial Potential of Betulinic Acid and Investigation of the Mechanism of Action against Nuclear and Metabolic Enzymes with Molecular Modeling

et al. 2023

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Natural products have important pharmacological activities. This study sought to investigate the activity of the compound betulinic acid (BA) against different strains of bacteria and fungi. The minimum inhibitory concentration (MIC) was determined and then the minimum bactericidal concentration (MBC) and minimum fungicidal concentration (MFC). After performing the in vitro tests, molecular modeling studies were carried out to investigate the mechanism of action of BA against the selected microorganisms. The results showed that BA inhibited the growth of microbial species. Among the 12 species (Staphylococcus aureus, S. epidermidis, Pseudomonas aeruginosa, Escherichia coli, Mycobacterium tuberculosis, Candida albicans, C. tropicalis, C. glabrata, Aspergillus flavus, Penicillium citrinum, Trichophyton rubrum, and Microsporum canis) investigated, 9 (75%) inhibited growth at a concentration of 561 µM and 1 at a concentration of 100 µM. In general, the MBC and MFC of the products were between 561 and 1122 μM. In silico studies showed that BA presented a mechanism of action against DNA gyrase and beta-lactamase targets for most of the bacteria investigated, while for fungi the mechanism of action was against sterol 14α-demethylase (CYP51) targets and dihydrofolate reductase (DHFR). We suggest that BA has antimicrobial activity against several species.

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“…Recent research demonstrated for the first time that Tafenoquine is effective against M.tb with lower MICs values compared to other antimalarial medications such as Chloroquine, Mefloquine, and Primaquine. Furthermore, Tafenoquine concentrations ranging from 1.25 to 80 μM had varying effects against sensitive and MDR strains of M.tb , ranging from moderate (reduction of 1.8 log CFU/mL) to strong bactericidal activity (reduction of 4.2 log CFU/ml) …”

Section: Repurposed Drug Candidates Against Tuberculosismentioning

confidence: 99%

“…Furthermore, Tafenoquine concentrations ranging from 1.25 to 80 μM had varying effects against sensitive and MDR strains of M.tb , ranging from moderate (reduction of 1.8 log CFU/mL) to strong bactericidal activity (reduction of 4.2 log CFU/ml). 61 …”

Section: Repurposed Drug Candidates Against Tuberculosismentioning

confidence: 99%

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade

et al. 2023

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The devastating impact of Tuberculosis (TB) has been a menace to mankind for decades. The World Health Organization (WHO) End TB Strategy aims to reduce TB mortality up to 95% and 90% of overall TB cases worldwide, by 2035. This incessant urge will be achieved with a breakthrough in either a new TB vaccine or novel drugs with higher efficacy. However, the development of novel drugs is a laborious process involving a timeline of almost 20−30 years with huge expenditure; on the other hand, repurposing previously approved drugs is a viable technique for overcoming current bottlenecks in the identification of new anti-TB agents. The present comprehensive review discusses the progress of almost all the repurposed drugs that have been identified to the present day (∼100) and are in the development or clinical testing phase against TB. We have also emphasized the efficacy of repurposed drugs in combination with already available frontline anti-TB medications along with the scope of future investigations. This study would provide the researchers a detailed overview of nearly all identified anti-TB repurposed drugs and may assist them in selecting the lead compounds for further in vivo/clinical research.

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Effects of tafenoquine against active, dormant and resistant Mycobacterium tuberculosis

Cited by 7 publications

References 15 publications

Repurposing of the antimalarial agent tafenoquine to combat MRSA

Repurposing of the antimalarial agent tafenoquine to combat MRSA

Antimicrobial Potential of Betulinic Acid and Investigation of the Mechanism of Action against Nuclear and Metabolic Enzymes with Molecular Modeling

Potential Repurposed Drug Candidates for Tuberculosis Treatment: Progress and Update of Drugs Identified in Over a Decade

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