Drug repurposing is gaining momentum due to the benefits of bypassing extensive preclinical testing, accelerating the progression to clinical efficacy trials and reducing the cost of drug development by at least 40%. The Seleem Laboratory has discovered and studied the mechanism of action of multiple FDA-approved drugs and clinical molecules to target multidrug-resistant pathogens. This work began with the drug simvastatin, a project that was funded with the assistance of a highly competitive Incentive Grant Proposal Category II) (1) . This work evolved into more complex studies (2-8). The Seleem lab was the first to identify the antimicrobial mechanism of action of several FDA-approved drugs and repurpose them for potential clinical trials(2-8). We are currently using different animal models in combination with molecular techniques to explore the potential of repurposed drugs to treat bacterial and fungal infections. These projects have been primarily funded by National Institutes of Health R56 and R01 grants.
Bacterial infection caused by intracellular pathogens, such as Mycobacterium, Salmonella, and Brucella, is a burgeoning global health epidemic that necessitates urgent action. However, the therapeutic value of a number of antibiotics, including aminoglycosides, against intracellular pathogenic bacteria is compromised due to their inability to traverse eukaryotic membranes. To address this problem, Dr. Seleem collaborates with Dr. Jean Chmielewski, a Distinguished Professor of Chemistry, to target intracellular pathogenic bacteria with cell penetrating synthetic peptides(9-11). The group has obtained NSF funding to support their research efforts on targeted delivery of antimicrobial peptides to kill intracellular pathogens. In addition, Drs. Seleem and Chmielewski collaborated with TSRL Inc., a privately-owned preclinical accelerator based in Ann Arbor, Michigan with a mission to advance promising therapeutics for treating severe and multi-drug resistant infections and subsequently obtained NIH STTR Award funding to expedite the preclinical development of a new class of cell-penetrating antimicrobial peptides that target intracellular bacterial pathogens, breakdown established biofilms, and reduce inflammatory cytokines common in complicated skin and soft tissue infections.
Intracellular bacterial infections are caused by bacteria that reside and multiply inside host cells such as macrophages to avoid detection and destruction by the host immune system. The therapeutic outcomes of traditional antibiotics treatment have not been satisfactory, because many antibiotics do not enter mammalian cells and access intracellular pathogens. Moreover, pathogens tend to develop resistance to antibiotic treatment as a consequence of persistent suboptimal delivery of antibiotics. For the effective management of intracellular bacterial infections, there is a critical unmet need for developing new types of antimicrobials with the appropriate delivery system which will effectively eradicate intracellular bacteria without inducing resistance. Seleem’s group, in collaboration with Dr. Yoon Yeo’s group at the Department of Industrial and Physical Pharmacy, is working on new solutions with novel carrier system that will deliver the new agents specifically to the infected macrophages and the pathogens resident in the cells. The group developed a pH-sensitive delivery system (semi-nanoparticles) to promote intracellular release of antimicrobials targeting intracellular pathogens (Brucella, Listeria, MRSA and Salmonella)(12). These projects are currently funded by National Science Foundation (NSF).
Every year, more than one million people in the United States are affected by bloodstream infections (BSI) and about 270,000 die as a result. Blood specimens are obtained and cultured for 1 to 5 days to determine the identity of existing pathogens and susceptibility to various antimicrobial agents. In an attempt to treat the infection before results of the culture come back, doctors often give patients antibiotics cocktail, hoping that one of the medications in the bunch will cure the patient. Often, it doesn’t, and sometimes patients are harmed by taking drugs they didn’t need. This practice also contributes to the increasing prevalence of antimicrobial resistance. For every hour of delay in starting correct antimicrobial therapy, the risk of death for a given patient with sepsis increases by 6% to 10%. Dr. Seleem has collaborated with Dr. Ji-Xin Cheng, Moustakas Chair Professor in Photonics and Optoelectronics at Boston University and world-wide leader in coherent Raman scattering microscopy, to focus on bloodstream infections and drug resistance. Drs. Seleem and Cheng with a $1.7 million grant from the National Institutes of Health are developing a microsecond-scale stimulated Raman spectroscopic imaging platform to enable in situ identification of a single bacterium/fungus in a complex environment at sub-micron resolution; along with early detection of its response to an antimicrobial drug(13, 14). This development will shift the paradigm of BSI diagnosis from a time-consuming, cultivation-dependent procedure to a culture-independent, in situ approach. Further clinical translation of the proposed technology would save patients’ lives with the early diagnosis of BSI and accurate profiling of a pathogen’s susceptibility to antimicrobials.
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. Our group is interested in antifungal drug discovery including testing and screening(15), identifying mechanism of action(16), reverting azole resistance(17), emerging fungal pathogen candida auris(18) and fungal biofilm (15).
In the area of de novo drug discovery, Dr. Seleem has collaborated with researchers at Purdue University as well as other national and international colleagues for antibacterial and antifungal drug discovery. Dr. Seleem currently has multiple collaborative de novo drug discovery projects with researchers nationally and internationally(15, 19-31).
We have an active drug discovery program with a focus on compounds active against Clostridium difficile, Neisseria gonorrhoeae, and Mycobacterium spp.(32).
We are engaged in research with several collaborators to develop, characterize and test novel therapeutic strategies for drug resistance pathogens.
1. Thangamani, S.; Mohammad, H.; Abushahba, M. F.; Hamed, M. I.; Sobreira, T. J.; Hedrick, V. E.; Paul, L. N.; Seleem, M. N. Exploring simvastatin, an antihyperlipidemic drug, as a potential topical antibacterial agent. Sci Rep 2015, 5, 16407.
2. Thangamani, S.; Mohammad, H.; Abushahba, M. F.; Sobreira, T. J.; Seleem, M. N. Repurposing auranofin for the treatment of cutaneous staphylococcal infections. Int J Antimicrob Agents 2016, 47, 195-201.
3. Thangamani, S.; Mohammad, H.; Abushahba, M. F.; Sobreira, T. J.; Hedrick, V. E.; Paul, L. N.; Seleem, M. N. Antibacterial activity and mechanism of action of auranofin against multi-drug resistant bacterial pathogens. Sci Rep 2016, 6, 22571.
4. Younis, W.; Thangamani, S.; Seleem, M. N. Repurposing Non-Antimicrobial Drugs and Clinical Molecules to Treat Bacterial Infections. Curr Pharm Des 2015, 21, 4106-11.
5. Thangamani, S.; Younis, W.; Seleem, M. N. Repurposing celecoxib as a topical antimicrobial agent. Front Microbiol 2015, 6, 750.
6. Thangamani, S.; Younis, W.; Seleem, M. N. Repurposing Clinical Molecule Ebselen to Combat Drug Resistant Pathogens. PLoS One 2015, 10, e0133877.
7. Thangamani, S.; Younis, W.; Seleem, M. N. Repurposing ebselen for treatment of multidrug-resistant staphylococcal infections. Sci Rep 2015, 5, 11596.
8. Thangamani, S.; Mohammad, H.; Younis, W.; Seleem, M. N. Drug repurposing for the treatment of staphylococcal infections. Curr Pharm Des 2015, 21, 2089-100.
9. Brezden, A.; Mohamed, M. F.; Nepal, M.; Harwood, J. S.; Kuriakose, J.; Seleem, M. N.; Chmielewski, J. Dual Targeting of Intracellular Pathogenic Bacteria with a Cleavable Conjugate of Kanamycin and an Antibacterial Cell-Penetrating Peptide. J Am Chem Soc 2016, 138, 10945-9.
10. Kuriakose, J.; Hernandez-Gordillo, V.; Nepal, M.; Brezden, A.; Pozzi, V.; Seleem, M. N.; Chmielewski, J. Targeting intracellular pathogenic bacteria with unnatural proline-rich peptides: coupling antibacterial activity with macrophage penetration. Angew Chem Int Ed Engl 2013, 52, 9664-7.
11. Nepal, M.; Mohamed, M. F.; Blade, R.; Eldesouky, H. E.; T, N. A.; Seleem, M. N.; Chmielewski, J. A Library Approach to Cationic Amphiphilic Polyproline Helices that Target Intracellular Pathogenic Bacteria. ACS Infect Dis 2018, 4, 1300-1305.
12. Pei, Y.; Mohamed, M. F.; Seleem, M. N.; Yeo, Y. Particle engineering for intracellular delivery of vancomycin to methicillin-resistant Staphylococcus aureus (MRSA)-infected macrophages. J Control Release 2017, 267, 133-143.
13. Hong, W.; Karanja, C. W.; Abutaleb, N. S.; Younis, W.; Zhang, X.; Seleem, M. N.; Cheng, J. X. Antibiotic Susceptibility Determination within One Cell Cycle at Single-Bacterium Level by Stimulated Raman Metabolic Imaging. Anal Chem 2018, 90, 3737-3743.
14. Karanja, C. W.; Hong, W.; Younis, W.; Eldesouky, H. E.; Seleem, M. N.; Cheng, J. X. Stimulated Raman Imaging Reveals Aberrant Lipogenesis as a Metabolic Marker for Azole-Resistant Candida albicans. Anal Chem 2017, 89, 9822-9829.
15. Ghosh, C.; Yadav, V.; Younis, W.; Mohammad, H.; Hegazy, Y. A.; Seleem, M. N.; Sanyal, K.; Haldar, J. Aryl-alkyl-lysines: Membrane-Active Fungicides That Act against Biofilms of Candida albicans. ACS Infect Dis 2017, 3, 293-301.
16. Mohammad, H.; Elghazawy, N. H.; Eldesouky, H. E.; Hegazy, Y. A.; Younis, W.; Avrimova, L.; Hazbun, T.; Arafa, R. K.; Seleem, M. N. Discovery of a Novel Dibromoquinoline Compound Exhibiting Potent Antifungal and Antivirulence Activity That Targets Metal Ion Homeostasis. ACS Infect Dis 2018, 4, 403-414.
17. Eldesouky, H. E.; Mayhoub, A.; Hazbun, T. R.; Seleem, M. N. Reversal of Azole Resistance in Candida albicans by Sulfa Antibacterial Drugs. Antimicrob Agents Chemother 2018, 62.
18. Eldesouky, H. E.; Li, X.; Abutaleb, N. S.; Mohammad, H.; Seleem, M. N. Synergistic interactions of sulfamethoxazole and azole antifungal drugs against emerging multidrug-resistant Candida auris. Int J Antimicrob Agents 2018.
19. Mohammad, H.; Mayhoub, A. S.; Ghafoor, A.; Soofi, M.; Alajlouni, R. A.; Cushman, M.; Seleem, M. N. Discovery and characterization of potent thiazoles versus methicillin- and vancomycin-resistant Staphylococcus aureus. J Med Chem 2014, 57, 1609-15.
20. Hagras, M.; Abutaleb, N. S.; Ali, A. O.; Abdel-Aleem, J. A.; Elsebaei, M. M.; Seleem, M. N.; Mayhoub, A. S. Naphthylthiazoles: Targeting Multidrug-Resistant and Intracellular Staphylococcus aureus with Biofilm Disruption Activity. ACS Infect Dis 2018.
21. Kotb, A.; Abutaleb, N. S.; Seleem, M. A.; Hagras, M.; Mohammad, H.; Bayoumi, A.; Ghiaty, A.; Seleem, M. N.; Mayhoub, A. S. Phenylthiazoles with tert-Butyl side chain: Metabolically stable with anti-biofilm activity. Eur J Med Chem 2018, 151, 110-120.
22. Elsebaei, M. M.; Mohammad, H.; Abouf, M.; Abutaleb, N. S.; Hegazy, Y. A.; Ghiaty, A.; Chen, L.; Zhang, J.; Malwal, S. R.; Oldfield, E.; Seleem, M. N.; Mayhoub, A. S. Alkynyl-containing phenylthiazoles: Systemically active antibacterial agents effective against methicillin-resistant Staphylococcus aureus (MRSA). Eur J Med Chem 2018, 148, 195-209.
23. Hagras, M.; Hegazy, Y. A.; Elkabbany, A. H.; Mohammad, H.; Ghiaty, A.; Abdelghany, T. M.; Seleem, M. N.; Mayhoub, A. S. Biphenylthiazole antibiotics with an oxadiazole linker: An approach to improve physicochemical properties and oral bioavailability. Eur J Med Chem 2018, 143, 1448-1456.
24. Eid, I.; Elsebaei, M. M.; Mohammad, H.; Hagras, M.; Peters, C. E.; Hegazy, Y. A.; Cooper, B.; Pogliano, J.; Pogliano, K.; Abulkhair, H. S.; Seleem, M. N.; Mayhoub, A. S. Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis. Eur J Med Chem 2017, 139, 665-673.
25. Mohammad, H.; Younis, W.; Ezzat, H. G.; Peters, C. E.; AbdelKhalek, A.; Cooper, B.; Pogliano, K.; Pogliano, J.; Mayhoub, A. S.; Seleem, M. N. Bacteriological profiling of diphenylureas as a novel class of antibiotics against methicillin-resistant Staphylococcus aureus. PLoS One 2017, 12, e0182821.
26. Hagras, M.; Mohammad, H.; Mandour, M. S.; Hegazy, Y. A.; Ghiaty, A.; Seleem, M. N.; Mayhoub, A. S. Investigating the Antibacterial Activity of Biphenylthiazoles against Methicillin- and Vancomycin-Resistant Staphylococcus aureus (MRSA and VRSA). J Med Chem 2017, 60, 4074-4085.
27. Eissa, I. H.; Mohammad, H.; Qassem, O. A.; Younis, W.; Abdelghany, T. M.; Elshafeey, A.; Abd Rabo Moustafa, M. M.; Seleem, M. N.; Mayhoub, A. S. Diphenylurea derivatives for combating methicillin- and vancomycin-resistant Staphylococcus aureus. Eur J Med Chem 2017, 130, 73-85.
28. Yahia, E.; Mohammad, H.; Abdelghany, T. M.; Fayed, E.; Seleem, M. N.; Mayhoub, A. S. Phenylthiazole antibiotics: A metabolism-guided approach to overcome short duration of action. Eur J Med Chem 2017, 126, 604-613.
29. Opoku-Temeng, C.; Naclerio, G. A.; Mohammad, H.; Dayal, N.; Abutaleb, N. S.; Seleem, M. N.; Sintim, H. O. N-(1,3,4-oxadiazol-2-yl)benzamide analogs, bacteriostatic agents against methicillin- and vancomycin-resistant bacteria. Eur J Med Chem 2018, 155, 797-805.
30. Yin, X.; Mohammad, H.; Eldesouky, H. E.; Abdelkhalek, A.; Seleem, M. N.; Dai, M. Rapid synthesis of bicyclic lactones via palladium-catalyzed aminocarbonylative lactonizations. Chem Commun (Camb) 2017, 53, 7238-7241.
31. Lv, W.; Banerjee, B.; Molland, K. L.; Seleem, M. N.; Ghafoor, A.; Hamed, M. I.; Wan, B.; Franzblau, S. G.; Mesecar, A. D.; Cushman, M. Synthesis of 3-(3-aryl-pyrrolidin-1-yl)-5-aryl-1,2,4-triazines that have antibacterial activity and also inhibit inorganic pyrophosphatase. Bioorg Med Chem 2014, 22, 406-18.
32. AbdelKhalek, A.; Abutaleb, N. S.; Mohammad, H.; Seleem, M. N. Antibacterial and antivirulence activities of auranofin against Clostridium difficile. Int J Antimicrob Agents 2018.
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