Update on Drug-Repurposing: Is it Useful for Tackling Antimicrobial Resistance?

Kaul, Grace; Shukla, Manjulika; Dasgupta, Arunava; Chopra, Sidharth

doi:10.2217/fmb-2019-0122

Cited by 37 publications

(36 citation statements)

References 20 publications

(20 reference statements)

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“…Mazumdar et al [ 35 ] demonstrated the role of DCF in the inhibition of DNA synthesis, in addition to a moderate membrane-damaging action against Listeria monocytogenes ATCC 51744. Similarly, several authors proposed the inhibition of DNA synthesis through binding to the DNA polymerase III β subunit as a mode of action of NSAIDs, preventing DNA replication and repair or impairment of membrane activity [ 26 , 36 , 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…In fact, preclinical, pharmacokinetic, pharmacodynamic and toxicity profiles and the side effects of these drugs are well known, which facilitates other therapeutic applications [ 19 , 25 ]. This pre-existing data allow skipping extensive phase I safety studies and starting clinical trials at phase IIa, reducing substantially the development time and cost [ 26 ]. In recent years, some studies acknowledged the antimicrobial effects of several classes of non-antibiotic drugs, more precisely, the nonsteroidal anti-inflammatory drugs (NSAIDs) [ 27 , 28 , 29 , 30 , 31 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

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NSAIDs as a Drug Repurposing Strategy for Biofilm Control

2020

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Persistent infections, usually associated with biofilm-producing bacteria, are challenging for both medical and scientific communities. The potential interest in drug repurposing for biofilm control is growing due to both disinvestment in antibiotic R&D and reduced efficacy of the available panel of antibiotics. In the present study, the antibacterial and antibiofilm activities of four non-steroidal anti-inflammatory drugs (NSAIDs), piroxicam (PXC), diclofenac sodium (DCF), acetylsalicylic acid (ASA) and naproxen sodium (NPX) were evaluated against Escherichia coli and Staphylococcus aureus. The minimum inhibitory/bactericidal concentrations (MICs and MBCs) and the dose–response curves from exposure to the selected NSAIDs were determined. MICs were found for PXC (800 μg/mL) and ASA (1750 μg/mL) against E. coli, and for DCF (2000 μg/mL) and ASA (2000 μg/mL) against S. aureus. No MBCs were found (>2000 μg/mL). The potential of NSAIDs to eradicate preformed biofilms was characterized in terms of biofilm mass, metabolic activity and cell culturability. Additionally, the NSAIDs were tested in combination with kanamycin (KAN) and tetracycline (TET). ASA, DCF and PXC promoted significant reductions in metabolic activity and culturability. However, only PXC promoted biofilm mass removal. Additive interactions were obtained for most of the combinations between NSAIDs and KAN or TET. In general, NSAIDs appear to be a promising strategy to control biofilms as they demonstrated to be more effective than conventional antibiotics.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

NSAIDs as a Drug Repurposing Strategy for Biofilm Control

2020

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“…In order to combat the increasing emergence of this fungal pathogen, it is imperative that new treatments be found. As opposed to a lengthy and expensive de novo pathway for drug discovery, repurposing or repositioning of existing drugs may represent a cost effective and faster approach to finding compounds with antifungal properties that can be readily used in patients [34][35][36][37]. To this end, here we screened The Pathogen Box ® library from Medicines for Malaria Venture (MMV; https://www.mmv.org/mmv-open/pathogen-box), a diverse library of approximately 400 drug-like compounds assembled by MMV, in search for inhibitors of C. auris.…”

Section: Introductionmentioning

confidence: 99%

Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture’s Pathogen Box

Wall

Herrera

Lopez-Ribot

2019

JoF

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Background. Candida auris has spread rapidly around the world as a causative agent of invasive candidiasis in health care facilities and there is an urgent need to find new options for treating this emerging, often multidrug-resistant pathogen. Methods. We screened the Pathogen Box® chemical library for inhibitors of C. auris strain 0390, both under planktonic and biofilm growing conditions. Results. The primary screen identified 12 compounds that inhibited at least 60% of biofilm formation or planktonic growth. After confirmatory dose-response assays, iodoquinol and miltefosine were selected as the two main leading repositionable compounds. Iodoquinol displayed potent in vitro inhibitory activity against planktonic C. auris but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of C. auris under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains C. auris clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of Candida, also with similar findings. Conclusion. Both drugs possess broad spectrum of activity against Candida spp., including multiple strains of the emergent C. auris, and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.

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“…This situation highlights the need to understand the mechanisms of drug resistance and tolerance, and the search for novel antifungal agents (62,63). As a few antifungal compounds are coming to market because their development is time-consuming and expensive, repositioning or repurposing drugs which are already licensed is an interesting and faster opportunity for the identification of novel antifungals agents (64)(65)(66). By using the repurposing strategy, many compounds have already been identified as new potential drugs against several diseases including parasitosis, protozooses and mycoses (64,(66)(67)(68)(69)(70)(71).…”

Section: Introductionmentioning

confidence: 99%

Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals the potential mechanism of action of miltefosine

Mac

et al. 2021

Preprint

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Aspergillus fumigatus is an important fungal pathogen and the main etiological agent of aspergillosis, a disease characterized by a noninvasive process that can evolve to a more severe clinical manifestation called invasive pulmonary aspergillosis (IPA) in immunocompromised patients. The antifungal arsenal to threat aspergillosis is very restricted. Azoles are the main therapeutic approach to control IPA, but the emergence of azole-resistant A. fumigatus isolates has significantly increased over the last decades. Therefore, new strategies are necessary to combat aspergillosis and drug repurposing has emerged as an efficient and alternative approach for identifying new antifungal drugs. Here, we used a screening approach to analyze A. fumigatus in vitro susceptibility to 1,127 compounds. A. fumigatus was more susceptible to 10 compounds, including miltefosine, a drug that displayed fungicidal activity against A. fumigatus. By screening an A. fumigatus transcription factor null library, we identified a single mutant, which has the rmiA (resistant to miltefosine) gene deleted, conferring a phenotype of susceptibility to miltefosine. The transcriptional profiling (RNA-seq) of the wild-type and the ΔrmiA strains and the Chromatin Immunoprecipitation coupled to next generation sequencing (ChIP-Seq) of a RmiA-tagged strain exposed to miltefosine revealed genes of the sphingolipids pathway that are directly or indirectly regulated by RmiA. Sphingolipids analysis demonstrated that the mutant has overall decreased levels of sphingolipids when growing in the presence of miltefosine. The identification of RmiA represents the first genetic element described and characterized which plays a direct role in miltefosine response in fungi.

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Update on Drug-Repurposing: Is it Useful for Tackling Antimicrobial Resistance?

Abstract: There are several advantages to drug repurposing including leveraging pre-existing safety and clinical data to skip extensive Phase I safety studies and enter clinical trials at Phase IIa, which not only positively impacts development times and costs but also negates risks "

Cited by 37 publications

References 20 publications

NSAIDs as a Drug Repurposing Strategy for Biofilm Control

NSAIDs as a Drug Repurposing Strategy for Biofilm Control

Repositionable Compounds with Antifungal Activity against Multidrug Resistant Candida auris Identified in the Medicines for Malaria Venture’s Pathogen Box

Screening of chemical libraries for new antifungal drugs against Aspergillus fumigatus reveals the potential mechanism of action of miltefosine

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