Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections

Holbrook, Selina Y. L.; Garzan, Atefeh; Dennis, Emily K.; Shrestha, Sanjib K.; Garneau‐Tsodikova, Sylvie

doi:10.1016/j.ejmech.2017.07.030

Cited by 43 publications

(38 citation statements)

References 43 publications

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“…A literature review was conducted to search for potential non-antimicrobial candidate drugs that are not intentionally used as antimicrobial agents but have one or more antimicrobial properties. A variety of drug families have been considered including: anthelmintics (Lim et al, 2013; Rajamuthiah et al, 2015; Gooyit and Janda, 2016; Joffe et al, 2017); anticancer drugs (Ueda et al, 2009; Butts et al, 2014; Yeo et al, 2018); anti-inflammatory/immunomodulatory drugs (Artini et al, 2014; Thangamani et al, 2015b; Ogundeji et al, 2016); antipsychotic and antidepressant drugs (Lieberman and Higgins, 2009; Andersson et al, 2016; Holbrook et al, 2017); statins (Parihar et al, 2014; Thangamani et al, 2015a; Ribeiro et al, 2017); and iron-storage drugs (Gi et al, 2014). While these drugs are approved for their clinical indications, promising antibacterial and antifungal activities have been reported in preclinical and clinical studies.…”

Section: Introductionmentioning

confidence: 99%

Drug Repurposing for the Treatment of Bacterial and Fungal Infections

2019

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Multidrug-resistant (MDR) pathogens pose a well-recognized global health threat that demands effective solutions; the situation is deemed a global priority by the World Health Organization and the European Centre for Disease Prevention and Control. Therefore, the development of new antimicrobial therapeutic strategies requires immediate attention to avoid the ten million deaths predicted to occur by 2050 as a result of MDR bacteria. The repurposing of drugs as therapeutic alternatives for infections has recently gained renewed interest. As drugs approved by the United States Food and Drug Administration, information about their pharmacological characteristics in preclinical and clinical trials is available. Therefore, the time and economic costs required to evaluate these drugs for other therapeutic applications, such as the treatment of bacterial and fungal infections, are mitigated. The goal of this review is to provide an overview of the scientific evidence on potential non-antimicrobial drugs targeting bacteria and fungi. In particular, we aim to: (i) list the approved drugs identified in drug screens as potential alternative treatments for infections caused by MDR pathogens; (ii) review their mechanisms of action against bacteria and fungi; and (iii) summarize the outcome of preclinical and clinical trials investigating approved drugs that target these pathogens.

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Section: Introductionmentioning

confidence: 99%

Drug Repurposing for the Treatment of Bacterial and Fungal Infections

2019

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“…Aripiprazole drug has shown the inhibition of hyphal formation which in turn reduces the biofilm formation in C. albicans (Rajasekharan et al 2019;Yousfi et al 2019). An antipsychotic drug named bromperidol was also reported to work synergistically with the azoles against C. albicans (Holbrook et al 2017). Thus repurposing of the licensed drugs could open new gates for therapeutics in combating fungal infections.…”

Section: Introductionmentioning

confidence: 99%

Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Singh

Fatima

Ahmad

et al. 2020

J. Appl. Microbiol.

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Aims Drug repurposing is an attractive chemotherapeutic strategy that serves to make up for the inadequacy of current antifungal drugs. The present study aims to repurpose theophylline (THP) against Candida albicans. THP is a methylxanthine derived from cocoa beans and tea extracts, generally used as the first‐line drug for asthma and other respiratory disorders. Methods and Results We investigated the antifungal activity of THP against C. albicans and non‐albicans species. Mechanistic insights revealed that THP induces membrane damage. Enhanced ionic disturbances and depleted ergosterol levels with the concomitant rise in membrane fluidity due to elevated flippase activity confirmed the membrane damaging effect. THP impeded the metabolic adaptability of C. albicans by inhibiting malate synthase and isocitrate lyase enzymes of the glyoxylate cycle. In vivo efficacy of THP was depicted by increased survival of C. albicans infected Caenorhabditis elegans model. Conclusions This study elucidates the antifungal potential of THP with mechanistic insights. Significance and Impact of the Study This study unveils the antifungal potential of THP, a known respiratory drug that can be further utilized for a wider range of applications such as combating fungal infections. The effect of THP with the known antifungal drugs can be exploited in the combinatorial drug approach for treating candidiasis.

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“…Unfortunately, resistance to these antifungal drugs has already been observed [ 35 ]. However, new strategies to combat fungal infections are being investigated, notably the development of derivatives of currently approved antifungals with improved activity and biological safety profiles [ 36 , 37 , 38 , 39 , 40 ], the combination therapy of current antifungal drugs working synergistically with other drugs [ 41 ], and the development of new classes of antifungal agents [ 42 ].…”

Section: Introductionmentioning

confidence: 99%

Differential Effects of Linkers on the Activity of Amphiphilic Tobramycin Antifungals

et al. 2018

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As the threat associated with fungal infections continues to rise and the availability of antifungal drugs remains a concern, it becomes obvious that the need to bolster the antifungal armamentarium is urgent. Building from our previous findings of tobramycin (TOB) derivatives with antifungal activity, we further investigate the effects of various linkers on the biological activity of these aminoglycosides. Herein, we analyze how thioether, sulfone, triazole, amide, and ether functionalities affect the antifungal activity of alkylated TOB derivatives against 22 Candida, Cryptococcus, and Aspergillus species. We also evaluate their impact on the hemolysis of murine erythrocytes and the cytotoxicity against mammalian cell lines. While the triazole linker appears to confer optimal activity overall, all of the linkers incorporated into the TOB derivatives resulted in compounds that are very effective against the Cryptococcus neoformans species, with MIC values ranging from 0.48 to 3.9 μg/mL.

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Repurposing antipsychotic drugs into antifungal agents: Synergistic combinations of azoles and bromperidol derivatives in the treatment of various fungal infections

Cited by 43 publications

References 43 publications

Drug Repurposing for the Treatment of Bacterial and Fungal Infections

Drug Repurposing for the Treatment of Bacterial and Fungal Infections

Repurposing of respiratory drug theophylline againstCandida albicans: mechanistic insights unveil alterations in membrane properties and metabolic fitness

Differential Effects of Linkers on the Activity of Amphiphilic Tobramycin Antifungals

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