Repositionable Compounds with Antifungal Activity Against Multidrug Resistant Identified in the Medicines for Malaria Venture's Pathogen Box

Overview

Journal J Fungi (Basel)

Date 2019 Oct 5

PMID 31581540

Citations 30

Authors

Gina Wall

Natalia Herrera

Jose L Lopez-Ribot

Affiliations

Soon will be listed here.

Abstract

Methods: We screened the Pathogen Box® chemical library for inhibitors of 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 but showed negligible inhibitory activity against biofilms; whereas miltefosine was able to inhibit the growth of under both planktonic and biofilm-growing conditions. Subsequent experiments confirmed their activity against nine other strains clinical isolates, irrespective of their susceptibility profiles against conventional antifungals. We extended our studies further to seven different species of , also with similar findings.

Conclusion: Both drugs possess broad spectrum of activity against spp., including multiple strains of the emergent , and may constitute promising repositionable options for the development of novel therapeutics for the treatment of candidiasis.

Citing Articles

Evaluation of MMV Pandemic Response Box compounds to identify potent compounds against clinically relevant bacterial and fungal clinical isolates .

Sivasankar S, Boppe A, Grobusch M, Jeyaraj S New Microbes New Infect. 2024; 60-61:101444.

PMID: 39040124 PMC: 11261442. DOI: 10.1016/j.nmni.2024.101444.

Strategies of Pharmacological Repositioning for the Treatment of Medically Relevant Mycoses.

Gomez-Gaviria M, Contreras-Lopez L, Aguilera-Dominguez J, Mora-Montes H Infect Drug Resist. 2024; 17:2641-2658.

PMID: 38947372 PMC: 11214559. DOI: 10.2147/IDR.S466336.

Accumulation of endogenous free radicals is required to induce titan-like cell formation in .

Garcia-Barbazan I, Torres-Cano A, Garcia-Rodas R, Sachse M, Luque D, Megias D mBio. 2023; 15(1):e0254923.

PMID: 38078728 PMC: 10790760. DOI: 10.1128/mbio.02549-23.

Development of an Imaging Flow Cytometry Method for Fungal Cytological Profiling and Its Potential Application in Antifungal Drug Development.

McMahon C, Esqueda M, Yu J, Wall G, Romo J, Vila T J Fungi (Basel). 2023; 9(7).

PMID: 37504711 PMC: 10381375. DOI: 10.3390/jof9070722.

Broad susceptibility of strains to 8-hydroxyquinolines and mechanisms of resistance.

Lohse M, Laurie M, Levan S, Ziv N, Ennis C, Nobile C mBio. 2023; 14(4):e0137623.

PMID: 37493629 PMC: 10470496. DOI: 10.1128/mbio.01376-23.

References

Ashburn T, Thor K . Drug repositioning: identifying and developing new uses for existing drugs. Nat Rev Drug Discov. 2004; 3(8):673-83. DOI: 10.1038/nrd1468. View

Adams E, Quinn M, Tsay S, Poirot E, Chaturvedi S, Southwick K . Candida auris in Healthcare Facilities, New York, USA, 2013-2017. Emerg Infect Dis. 2018; 24(10):1816-1824. PMC: 6154128. DOI: 10.3201/eid2410.180649. View

Rutala W, Kanamori H, Gergen M, Sickbert-Bennett E, Weber D . Susceptibility of Candida auris and Candida albicans to 21 germicides used in healthcare facilities. Infect Control Hosp Epidemiol. 2019; 40(3):380-382. DOI: 10.1017/ice.2019.1. View

Kean R, Sherry L, Townsend E, McKloud E, Short B, Akinbobola A . Surface disinfection challenges for Candida auris: an in-vitro study. J Hosp Infect. 2017; 98(4):433-436. DOI: 10.1016/j.jhin.2017.11.015. View

Veale C . Unpacking the Pathogen Box-An Open Source Tool for Fighting Neglected Tropical Disease. ChemMedChem. 2019; 14(4):386-453. DOI: 10.1002/cmdc.201800755. View

Kean R, Ramage G . Combined Antifungal Resistance and Biofilm Tolerance: the Global Threat of Candida auris. mSphere. 2019; 4(4). PMC: 6669339. DOI: 10.1128/mSphere.00458-19. View

Ledwoch K, Maillard J . Dry Surface Biofilm (DSB) for Disinfectant Efficacy Testing. Materials (Basel). 2018; 12(1). PMC: 6337396. DOI: 10.3390/ma12010018. View

Ramage G, Vandewalle K, Wickes B, Lopez-Ribot J . Characteristics of biofilm formation by Candida albicans. Rev Iberoam Micol. 2004; 18(4):163-70. View

Arauz A, Caceres D, Santiago E, Armstrong P, Arosemena S, Ramos C . Isolation of Candida auris from 9 patients in Central America: Importance of accurate diagnosis and susceptibility testing. Mycoses. 2017; 61(1):44-47. DOI: 10.1111/myc.12709. View

10.

Bhattacharya S, Jha T, Sundar S, Thakur C, Engel J, Sindermann H . Efficacy and tolerability of miltefosine for childhood visceral leishmaniasis in India. Clin Infect Dis. 2003; 38(2):217-21. DOI: 10.1086/380638. View

11.

Pierce C, Uppuluri P, Tristan A, Wormley Jr F, Mowat E, Ramage G . A simple and reproducible 96-well plate-based method for the formation of fungal biofilms and its application to antifungal susceptibility testing. Nat Protoc. 2008; 3(9):1494-500. PMC: 2741160. DOI: 10.1038/nport.2008.141. View

12.

Verweij J, Planting A, van der Burg M, Stoter G . A dose-finding study of miltefosine (hexadecylphosphocholine) in patients with metastatic solid tumours. J Cancer Res Clin Oncol. 1992; 118(8):606-8. DOI: 10.1007/BF01211805. View

13.

Lockhart S . Candida auris and multidrug resistance: Defining the new normal. Fungal Genet Biol. 2019; 131:103243. DOI: 10.1016/j.fgb.2019.103243. View

14.

Sarma S, Upadhyay S . Current perspective on emergence, diagnosis and drug resistance in . Infect Drug Resist. 2017; 10:155-165. PMC: 5476417. DOI: 10.2147/IDR.S116229. View

15.

Lockhart S, Etienne K, Vallabhaneni S, Farooqi J, Chowdhary A, Govender N . Simultaneous Emergence of Multidrug-Resistant Candida auris on 3 Continents Confirmed by Whole-Genome Sequencing and Epidemiological Analyses. Clin Infect Dis. 2016; 64(2):134-140. PMC: 5215215. DOI: 10.1093/cid/ciw691. View

16.

de Oliveira H, Monteiro M, Rossi S, Peman J, Ruiz-Gaitan A, Mendes-Giannini M . Identification of Off-Patent Compounds That Present Antifungal Activity Against the Emerging Fungal Pathogen . Front Cell Infect Microbiol. 2019; 9:83. PMC: 6454888. DOI: 10.3389/fcimb.2019.00083. View

17.

Smorenburg C, Seynaeve C, Bontenbal M, Planting A, Sindermann H, Verweij J . Phase II study of miltefosine 6% solution as topical treatment of skin metastases in breast cancer patients. Anticancer Drugs. 2001; 11(10):825-8. DOI: 10.1097/00001813-200011000-00006. View

18.

Soto J, Arana B, Toledo J, Rizzo N, Vega J, Diaz A . Miltefosine for new world cutaneous leishmaniasis. Clin Infect Dis. 2004; 38(9):1266-72. DOI: 10.1086/383321. View

19.

Piedrahita C, Cadnum J, Jencson A, Shaikh A, Ghannoum M, Donskey C . Environmental Surfaces in Healthcare Facilities are a Potential Source for Transmission of Candida auris and Other Candida Species. Infect Control Hosp Epidemiol. 2017; 38(9):1107-1109. DOI: 10.1017/ice.2017.127. View

20.

Burnett B, Mitchell C . Antimicrobial activity of iodoquinol 1%-hydrocortisone acetate 2% gel against ciclopirox and clotrimazole. Cutis. 2008; 82(4):273-80. View