Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis
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Globally, invasive fungal infections pose a significant challenge to modern human medicine due to the limited number of antifungal drugs and the rise in resistance to current antifungal agents. A vast majority of invasive fungal infections are caused by species of Candida, Cryptococcus, and Aspergillus. Novel antifungal molecules consisting of unexploited chemical scaffolds with a unique mechanism are a pressing need. The present study identifies a dibromoquinoline compound (4b) with broad-spectrum antifungal activity that inhibits the growth of pertinent species of Candida (chiefly C. albicans), Cryptococcus, and Aspergillus at a concentration of as low as 0.5 μg/mL. Furthermore, 4b, at a subinhibitory concentration, interfered with the expression of two key virulence factors (hyphae and biofilm formation) involved in C. albicans pathogenesis. Three yeast deletion strains ( cox17Δ, ssa1Δ, and aft2Δ) related to metal ion homeostasis were found to be highly sensitive to 4b in growth assays, indicating that the compound exerts its antifungal effect through a unique, previously unexploited mechanism. Supplementing the media with either copper or iron ions reversed the strain sensitivity to 4b, further corroborating that the compound targets metal ion homeostasis. 4b's potent antifungal activity was validated in vivo, as the compound enhanced the survival of Caenorhabditis elegans infected with fluconazole-resistant C. albicans. The present study indicates that 4b warrants further investigation as a novel antifungal agent.
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Only three classes of systemic antifungal drugs (azoles, polyenes, echinocandins) are available for treatment of invasive Candida infections.
“Currently, only three classes of systemic antifungal drugs (azoles, polyenes, and echinocandins) are available for the treatment of invasive Candida infections [9].”
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Cites
Robinson, M. D., McCarthy, D. J., & Smyth, G. K. (2010) · Bioinformatics · doi:10.1093/bioinformatics/btp616 · Cited by 41,364 · see citing works
Wisplinghoff, H., Bischoff, T., Tallent, S. M., Seifert, H., Wenzel, R. P., & Edmond, M. B. (2004) · Clinical Infectious Diseases · doi:10.1086/421946 · Cited by 4,496 · see citing works
Hidden Killers: Human Fungal Infections
Brown, G. D., Denning, D. W., Gow, N. A. R., Levitz, S. M., Netea, M. G., & White, T. C. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004404 · Cited by 4,284 · see citing works
Microtiter Dish Biofilm Formation Assay
O’Toole, G. A. (2011) · Journal of Visualized Experiments · doi:10.3791/2437 · Cited by 2,184 · see citing works
Park, B. J., Wannemuehler, K. A., Marston, B. J., Govender, N. P., Pappas, P. G., & Chiller, T. M. (2009) · AIDS · doi:10.1097/qad.0b013e328322ffac · Cited by 2,013 · see citing works
Methods in yeast genetics : a Cold Spring Harbor Laboratory course manual
Amberg, D. C., Burke, D. J., & Strathern, J. N. (2005) · Cited by 1,853 · see citing works
Pappas, P. G., Alexander, B. D., Andes, D. R., Hadley, S., Kauffman, C. A., Freifeld, A., Anaissie, E. J., Brumble, L. M., Herwaldt, L., Ito, J., et al. (2010) · Clinical Infectious Diseases · doi:10.1086/651262 · Cited by 1,570 · see citing works
Sardi, J. C. O., Scorzoni, L., Bernardi, T., Fusco-Almeida, A. M., & Mendes Giannini, M. J. S. (2013) · Journal of Medical Microbiology · doi:10.1099/jmm.0.045054-0 · Cited by 1,184 · see citing works
Pierce, C. G., Uppuluri, P., Tristan, A. R., Wormley, F. L., Mowat, E., Ramage, G., & Lopez-Ribot, J. L. (2008) · Nature Protocols · doi:10.1038/nprot.2008.141 · Cited by 1,041 · see citing works
Candidalysin is a fungal peptide toxin critical for mucosal infection
Moyes, D. L., Wilson, D., Richardson, J. P., Mogavero, S., Tang, S. X., Wernecke, J., Hoefs, S., Gratacap, R. L., Robbins, J., Runglall, M., et al. (2016) · Nature · doi:10.1038/nature17625 · Cited by 928 · see citing works
Antifungal drug resistance: mechanisms, epidemiology, and consequences for treatment
Pfaller, M. A. (2012) · The American Journal of Medicine · doi:10.1016/j.amjmed.2011.11.001 · Cited by 903 · see citing works
The antifungal pipeline: a reality check
Perfect, J. R. (2017) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2017.46 · Cited by 866 · see citing works
Kuhn, D. M., George, T., Chandra, J., Mukherjee, P. K., & Ghannoum, M. A. (2002) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.46.6.1773-1780.2002 · Cited by 765 · see citing works
Saville, S. P., Lazzell, A. L., Monteagudo, C., & Lopez-Ribot, J. L. (2003) · Eukaryotic Cell · doi:10.1128/ec.2.5.1053-1060.2003 · Cited by 655 · see citing works
Antifungal Drug Development: Challenges, Unmet Clinical Needs, and New Approaches
Roemer, T., & Krysan, D. J. (2014) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a019703 · Cited by 593 · see citing works
Chemogenomic profiling: Identifying the functional interactions of small molecules in yeast
Giaever, G. N., Flaherty, P., Kumm, J., Proctor, M. J., Nislow, C., Jaramillo, D. F., Chu, A. M., Jordan, M. I., Arkin, A. P., & Davis, R. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307490100 · Cited by 506 · see citing works
How to bolster the antifungal pipeline
Denning, D. W., & Bromley, M. (2015) · Science · doi:10.1126/science.aaa6097 · Cited by 481 · see citing works
Quantitative phenotyping via deep barcode sequencingPreprint
Smith, A. M., Heisler, L. E., Mellor, J. C., Kaper, F., Thompson, M. J., Chee, M. S., Roth, F. P., Giaever, G. N., & Nislow, C. (2009) · Genome Research · doi:10.1101/gr.093955.109 · Cited by 297 · see citing works
Identification of novel antimicrobials using a live-animal infection model
Moy, T. I., Ball, A. R., Anklesaria, Z., Casadei, G., Lewis, K., & Ausubel, F. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0604055103 · Cited by 289 · see citing works
Pfaller, M. A., Diekema, D. J., Gibbs, D. L., Newell, V. A., Nagy, E., Dobiášová, S., Rinaldi, M. G., Barton, R., Veselov, A. V., & the Global Antifungal Surveillance Group (2007) · Journal of Clinical Microbiology · doi:10.1128/jcm.01915-07 · Cited by 268 · see citing works
Martins, M., Uppuluri, P., Thomas, D. P., Cleary, I. A., Henriques, M., Lopez-Ribot, J. L., & Oliveira, R. (2010) · Mycopathologia · doi:10.1007/s11046-009-9264-y · Cited by 250 · see citing works
Mukaremera, L., Lee, K. K., Mora-Montes, H. M., & Gow, N. A. R. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00629 · Cited by 202 · see citing works
Inhibitory Effect of Sophorolipid on Candida albicans Biofilm Formation and Hyphal Growth
Haque, F., Alfatah, M., Ganesan, K., & Bhattacharyya, M. S. (2016) · Scientific Reports · doi:10.1038/srep23575 · Cited by 192 · see citing works
Nett, J. E., Sanchez, H., Cain, M. T., Ross, K. M., & Andes, D. R. (2011) · Eukaryotic Cell · doi:10.1128/ec.05126-11 · Cited by 168 · see citing works
Antifungal susceptibility of Candida albicans in biofilms
Tobudic, S., Kratzer, C., Lassnigg, A. M., & Presterl, E. (2011) · Mycoses · doi:10.1111/j.1439-0507.2011.02076.x · Cited by 165 · see citing works
Menzel, R., Bogaert, T., & Achazi, R. K. (2001) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.2001.2568 · Cited by 161 · see citing works
Nobile, C. J., Solis, N., Myers, C. L., Fay, A. J., Deneault, J.-S., Nantel, A., Mitchell, A. P., & Filler, S. G. (2008) · Cellular Microbiology · doi:10.1111/j.1462-5822.2008.01198.x · Cited by 150 · see citing works
Tackling Fungal Resistance by Biofilm Inhibitors
Wu, S., Wang, Y., Liu, N., Dong, G., & Sheng, C. (2017) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.6b01203 · Cited by 134 · see citing works
C. elegans: model host and tool for antimicrobial drug discovery
Ewbank, J. J., & Zugasti, O. (2011) · Disease Models & Mechanisms · doi:10.1242/dmm.006684 · Cited by 118 · see citing works
Thangamani, S., Eldesouky, H. E., Mohammad, H. T., Pascuzzi, P. E., Avramova, L. V., Hazbun, T. R., & Seleem, M. N. (2016) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2016.09.029 · Cited by 113 · see citing works
Self-citationMohammad, H. T., Mayhoub, A. S., Ghafoor, A., et al. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm401905m · Cited by 109 · see citing works
Self-citationAntifungal Quinoline Alkaloids from Waltheria indica
Cretton, S., Dorsaz, S., Azzollini, A., Favre-Godal, Q., Marcourt, L., Ebrahimi, S. N., Voinesco, F., Michellod, E., Sanglard, D., Gindro, K., et al. (2016) · Journal of Natural Products · doi:10.1021/acs.jnatprod.5b00896 · Cited by 104 · see citing works
Butts, A., Koselny, K., Chabrier-Roselló, Y., Semighini, C. P., Brown, J. C. S., Wang, X., Annadurai, S., DiDone, L., Tabroff, J., Childers, W. E., et al. (2014) · mBio · doi:10.1128/mbio.00765-13 · Cited by 102 · see citing works
Antimicrobial Activities of Mefloquine and a Series of Related Compounds
Kunin, C. M., & Ellis, W. Y. (2000) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.44.4.848-852.2000 · Cited by 100 · see citing works
Thangamani, S., Maland, M., Mohammad, H., Pascuzzi, P. E., Avramova, L., Koehler, C. M., Hazbun, T. R., & Seleem, M. N. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00004 · Cited by 90 · see citing works
Self-citationKoselny, K., Green, J., DiDone, L., Halterman, J. P., Fothergill, A. W., Wiederhold, N. P., Patterson, T. F., Cushion, M. T., Rappelye, C., Wellington, M., et al. (2016) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.01061-16 · Cited by 83 · see citing works
Cheng, Y., Avula, S. R., Gao, W., Addla, D., Tangadanchu, V. K. R., Zhang, L., Lin, J.-M., & Zhou, C. (2016) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2016.10.011 · Cited by 78 · see citing works
Irfan, M. A., Alam, S., Manzoor, N., & Abid, M. (2017) · PLoS ONE · doi:10.1371/journal.pone.0175710 · Cited by 51 · see citing works
Mohammad, H. T., Cushman, M., & Seleem, M. N. (2015) · PLoS ONE · doi:10.1371/journal.pone.0142321 · Cited by 44 · see citing works
Self-citationExploratory analysis of kinetic solubility measurements of a small molecule library
Guha, R., Dexheimer, T. S., Kestranek, A., Jadhav, A., Chervenak, A., Ford, M. G., Simeonov, A. M., Roth, G. P., & Thomas, C. J. (2011) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2011.05.005 · Cited by 40 · see citing works
Chang, W., Zhang, M., Li, Y., Li, X., Gao, Y., Xie, Z., & Lou, H. (2015) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2015.05.005 · Cited by 36 · see citing works
Strategies in the Discovery of Novel Antifungal Scaffolds
Liu, N., Wang, C., Su, H., Zhang, W., & Sheng, C. (2016) · Future Medicinal Chemistry · doi:10.4155/fmc-2016-0020 · Cited by 34 · see citing works
In vitro analysis of flufenamic acid activity against Candida albicans biofilms
Chavez-Dozal, A. A., Jahng, M., Rane, H. S., Asare, K., Kulkarny, V. V., Bernardo, S. M., & Lee, S. A. (2014) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2013.08.018 · Cited by 26 · see citing works
Madariaga, F., Fernández-Soto, R., Duarte, L. F., Suarez, N., Delgadillo, D., Jara, J. A., Fernández‐Ramires, R., Urzúa, B., & Molina‐Berríos, A. (2017) · PLoS ONE · doi:10.1371/journal.pone.0176755 · Cited by 26 · see citing works
Rouabhia, M., Semlali, A., Chandra, J., Mukherjee, P. K., Chmielewski, W., & Ghannoum, M. A. (2012) · Mediators of Inflammation · doi:10.1155/2012/398207 · Cited by 19 · see citing works
The Effect of 5-Fluorocytosine on the Blastospores and Hyphae of Candida Albicans
Polak, A., & Wain, W. H. (1979) · Journal of Medical Microbiology · doi:10.1099/00222615-12-1-83 · Cited by 19 · see citing works
van der Auwera, P., Ceuppens, A. M., Heymans, C., & Meunier, F. (1986) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.29.6.997 · Cited by 17 · see citing works
New trifluoromethyl quinolone derivatives: Synthesis and investigation of antimicrobial properties
Panda, S. S., & Jain, S. C. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.03.120 · Cited by 17 · see citing works
MORTALITY AFTER CLINICAL MANAGEMENT OF AIDS-ASSOCIATED CRYPTOCOCCAL MENINGITIS IN KENYA.
Baldassarre, R., Mdodo, R., Omonge, E., et al. (2014) · PubMed · Cited by 15 · see citing works
Elghazawy, N. H., Hefnawy, A., Sedky, N. K., et al. (2017) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2017.05.036 · Cited by 14 · see citing works
Self-citationWhole animal HTS of small molecules for antifungal compounds
Muhammed, M., Arvanitis, M., & Mylonakis, E. E. (2015) · Expert Opinion on Drug Discovery · doi:10.1517/17460441.2016.1122591 · Cited by 13 · see citing works
Garudachari, B., Isloor, A. M., Satyanarayana, M. N., et al. (2013) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2013.07.021 · Cited by 10 · see citing works
The effect of flucytosine on the germination of Candida albicans
Wain, W. H., & Polak, A. (1979) · Postgraduate Medical Journal · doi:10.1136/pgmj.55.647.671 · Cited by 5 · see citing works
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- [56]Amberg DC BD Strathern JN 2005 Methods in Yeast Genetics Cold Spring Harbor Laboratory Press New York, NY
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Eldesouky, H. E., Li, X., Abutaleb, N. S., Mohammad, H., & Seleem, M. N. (2018) · International Journal of Antimicrobial Agents · doi:10.1016/j.ijantimicag.2018.08.016 · Cited by 90 · see citing works
Self-citationEldesouky, H. E., Salama, E. A., Li, X., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N. (2020) · Scientific Reports · doi:10.1038/s41598-020-64571-7 · Cited by 55 · see citing works
Self-citationEldesouky, H. E., Salama, E. A., Lanman, N. A., Hazbun, T. R., & Seleem, M. N. (2020) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00684-20 · Cited by 56 · see citing works
Self-citationEldesouky, H. E., Lanman, N. A., Hazbun, T. R., & Seleem, M. N. (2020) · Virulence · doi:10.1080/21505594.2020.1838741 · Cited by 37 · see citing works
Self-citationEldesouky, H. E., Salama, E. A., Hazbun, T. R., Mayhoub, A. S., & Seleem, M. N. (2020) · Scientific Reports · doi:10.1038/s41598-020-62976-y · Cited by 33 · see citing works
Self-citationZinc and Iron Homeostasis: Target-Based Drug Screening as New Route for Antifungal Drug Development
Simm, C., & May, R. C. (2019) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2019.00181 · Cited by 26 · see citing works
Salama, E. A., Elgammal, Y., Wijeratne, A., Lanman, N. A., Utturkar, S. M., Farhangian, A., Li, J., Meunier, B., Hazbun, T. R., & Seleem, M. N. (2024) · Emerging Microbes & Infections · doi:10.1080/22221751.2024.2322649 · Cited by 16 · see citing works
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- Authors
- Mohammad, H., Elghazawy, N. H., Eldesouky, H. E., Hegazy, Y. A., Younis, W., Avrimova, L., Hazbun, T., Arafa, R. K., & Seleem, M. N.
- Affiliations
- Purdue University West Lafayette (US)
- Zewail City of Science and Technology (EG)
- Corresponding author
- Arafa, Reem K.
- Seleem, Mohamed N.
- ORCID
- Venue
- ACS Infectious Diseases
- Publisher
- American Chemical Society (ACS)
- Published
- 2018-01-25
- Volume
- 4
- Issue
- 3
- Pages
- 403-414
- ISSN
- 2373-8227 (ISSN-L)
- PMC
- PMC5903683
- OpenAlex
- W2785064310
- Cited by
- 29
- References
- 53
- Citations by year
- 2025: 2 · 2024: 5 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 2
- FWCI
- 3.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Allergy and Infectious Diseases (R01AI130186)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Antifungal resistance and susceptibility
- Life Sciences › Agricultural and Biological Sciences › Ecology, Evolution, Behavior and Systematics › Fungal Plant Pathogen Control
- Physical Sciences › Chemistry › Organic Chemistry › Antimicrobial agents and applications
- Keywords
- antifungal agents, Candida albicans, metal homeostasis, virulence factor inhibition, hyphal development, biofilm formation, Cox17, Ssa1, copper, iron, fluconazole resistance, invasive fungal infections, Caenorhabditis elegans infection model
- MeSH terms
- Animals, Antifungal Agents, Aspergillus, Candida, Cryptococcus, Culture Media, Disease Models, Animal, Homeostasis, Ions, Metals, Mycoses, Quinolines, Survival Analysis, Caenorhabditis elegans
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