Invasive fungal infections are difficult to treat due to the increasing resistance of fungal species to current treatment and the limited number of available antifungal drugs.1,2 In December 2022, World Health Organization (WHO) published the first list of priority fungal infections threatening public health.3 Pathogenic fungi cause the most significant burden among susceptible individuals, e.g., immunocompromised, organ transplants, or cancer patients. Presence of fungal strains resistant to clinically used antifungals represents the biggest challenge of current decade.
Fungal pathogens use several mechanisms leading to drug resistance ranging from drug efflux to chromosomal duplication or target site mutation.4,5 Moreover, resistant invasive mycoses can also develop secondary resistance in response to the current treatment.6,7 Several species (e.g., Aspergillus) have reduced susceptibility to the currently used antifungal drugs resulting in pan-resistance. Prodruging current antifungal drugs overrides toxicity of drugs and drug resistance of fungal pathogens by circumventing common biological barriers, and consequently saves time and money in developing new chemical entities.
Figure 1. a) Isavuconazole prodrug (Isavuconazolium sulfate, active drug isavuconazole is released by activation through plasma esterases). b) Permanent modification of Amphotericin B (AmB) leads to less toxic antifungals, secondarily lowering drug resistance.
Aim of this proposal is the synthesis and development of non-targeted prodrugs of FDA-approved antifungal drugs to improve their pharmacokinetic properties, e.g., increasing solubility and lowering toxicity. The design of prodrugs will be part of the research (here, we built on our previous experience in the design of azole hybrids, prodrugs, and self-immolative linkers). The second part of the research project will be the design and synthesis of targeted prodrugs that are recognized specifically by fungal pathogens. The applicant should have good experience in both theoretical and practical organic chemistry.
1) M. Hoenigl, R. Sprute, M. Egger, A. Arastehfar, O. A. Cornely, R. Krause, C. Lass-Flörl, J. Prattes, A. Spec, G. R. Thompson, N. Wiederhold, J. D. Jenks, Drugs 2021, 81, 1703–1729.
2) W. Liu, L. Yuan, S. Wang, J. Med. Chem. 2020, 63, 12429–12459.
3) “WHO fungal priority pathogens list to guide research, development and public health action,” can be found under https://www.who.int/publications/i/item/9789240060241.
4) T. Y. Hargrove, L. Friggeri, Z. Wawrzak, A. Qi, W. J. Hoekstra, R. J. Schotzinger, J. D. York, F. Peter Guengerich, G. I. Lepesheva, J. Biol. Chem.2017, 292, 6728–6743.
5) W. Chang, J. Liu, M. Zhang, H. Shi, S. Zheng, X. Jin, Y. Gao, S. Wang, A. Ji, H. Lou, Nat. Commun. 2018, 91, 1–12.
6) L. W. Cheng, K. Land, Pharm. 2022, 15, 482.
7) M. A. Ghannoum, Y. Fu, A. S. Ibrahim, L. A. Mortara, M. C. Shafiq, J. E. Edwards, R. S. Criddle, Antimicrob. Agents Chemother. 1995, 39, 2459–2465.
8) a) P. Šimon, M. Tichotová, M. G. Gallardo, E. Procházková, O. Baszczyňski,Chem. Eur. J. 2021, 27(50), 12763–12775. b) E. Procházková, P. Šimon, M. Straka, J. Filo, M. Májek, M. Cigáň, O. Baszczyňski, Chem. Commun. 2021, 57, 211-214. c) O. Štěpánek, A. Čmoková, E. Procházková, V. Grobárová, J. Černý, M. Slapničková, A. Zíková, M. Kolařík, O. Baszczyňski, ChemMedChem 2022, e202200385.
Workplace: Department of Organic Chemistry, Faculty of Science, Charles University
Contact/supervisor: Ing. Ondřej Baszczyňski, Ph.D.
Position available from: January 1, 2024 (for 2 years)
Deadline date for applications: 25th July, 2023