Aminoglycoside-based antibiotic adjuvants: a platform for drug discovery

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dc.contributor.authorIdowu, Temilolu
dc.contributor.examiningcommitteeZhanel, George G. (Medical Microbiology/Infectious Diseases)en_US
dc.contributor.examiningcommitteeKumar, Ayush (Microbiology)en_US
dc.contributor.examiningcommitteeStetefeld, Jörg (Biochemistry)en_US
dc.contributor.examiningcommitteeDavis, Rebecca (Chemistry)en_US
dc.contributor.examiningcommitteeFridman, Micha ( Chemistry, Tel Aviv University)en_US
dc.contributor.supervisorSchweizer, Frank (Chemistry)en_US
dc.date.accessioned2019-08-26T18:29:46Z
dc.date.available2019-08-26T18:29:46Z
dc.date.issued2019-08-19en_US
dc.date.submitted2019-08-19T20:24:44Zen
dc.degree.disciplineChemistryen_US
dc.degree.levelDoctor of Philosophy (Ph.D.)en_US
dc.description.abstractAntimicrobial resistance is a global phenomenon that poses a serious threat to public health. Pathogenic bacteria express multiple resistance mechanisms that work concertedly to shield them from antibiotics. Prior works have identified several signature pathways by which Gram-negative bacteria become refractory to available treatment options. One of such is the chromosomally-encoded intrinsic mechanism of resistance – defined by reduced outer membrane (OM) permeability and over-expressed efflux pumps. Aminoglycosides are an interesting class of Gram-negative-active agents because of their pleiotropic mechanism of action. They are polybasic hydrophilic molecules that permeate the OM by displacing divalent cations responsible for maintaining OM integrity, in a concentration-dependent manner. Next, they navigate the hydrophobic inner membrane via an energy-dependent process. Thirdly, they inhibit the fidelity of ribosomal protein translation at low concentrations. Lastly, they can also disrupt the integrity of the OM at higher concentrations. Unsurprisingly, the response of bacteria to this class of drugs is efficient, holistic, and co-ordinated. My doctoral work describes efforts directed at uncoupling the multifunctional properties of aminoglycosides, with a view to abolishing ribosomal effects and amplifying OM permeabilizing properties. As a representative example, I thoroughly explored the chemistry of tobramycin and prepared series of tobramycin-based conjugates with different spectrum of activity. Mechanistic studies to understand their mode(s) of action, pattern of synergism, and mechanism of resistance development were conducted. Preliminary in vivo efficacies were evaluated using a Galleria mellonella infection model. Toxicological liabilities of the newly synthesized molecules were also investigated. In summary, our campaign led to the discovery of a novel broad-spectrum homodimeric tobramycin-based scaffold that is non-toxic and more potent than the current gold standard potentiator molecule, polymyxin B nonapeptide. We also identified a non-toxic narrow-spectrum tobramycin-cyclam conjugate that restores full antibiotic potency of -lactam antibiotics against recalcitrant P. aeruginosa. This study expands our understanding of the multifunctional properties of aminoglycosides, hints at how we can win a war by losing a battle and provides a template to exploit the resistance pathways of bacteria to mine novel therapeutics. It is hoped that this study, and the concepts therein, will contribute meaningfully towards combating the threats of antimicrobial resistance.en_US
dc.description.noteOctober 2019en_US
dc.identifier.citationIdowu, T.; Ammeter, D.; Arthur, G.; Zhanel, G. G.; Schweizer, F. Potentiation of β-Lactam Antibiotics and β-Lactam/β-Lactamase Inhibitor Combinations against Multidrug and Extensively Drug-Resistant Pseudomonas aeruginosa using Non-Ribosomal Tobramycin–Cyclam Conjugates. J. Antimicrob. Chemother. 2019, doi.org/10.1093/jac/dkz228en_US
dc.identifier.citationIdowu, T.; Arthur, G.; Zhanel, G. G.; Schweizer, F. Heterodimeric Rifampicin–Tobramycin Conjugates Break Intrinsic Resistance of Pseudomonas aeruginosa to Doxycycline and Chloramphenicol in Vitro and in a Galleria mellonella in Vivo Model. Eur. J. Med. Chem. 2019, 174, 16–32.en_US
dc.identifier.citationIdowu, T.; Ammeter, D., Rossong, R.; Zhanel, G. G.; Schweizer, F. Homodimeric Tobramycin Adjuvants Repurposes Novobiocin as an Effective Antibacterial Agent against Gram-negative Bacteria. J. Med. Chem. 2019en_US
dc.identifier.citationAmmeter, D.; Idowu, T.; Zhanel, G. G.; Schweizer, F. Development of a Nebramine–Cyclam Conjugate as an Antibacterial Adjuvant to Potentiate β-Lactam Antibiotics against Multidrug-Resistant P. aeruginosa. Journal of Antibiotics 2019. https://doi.org/10.1038/s41429-019-0221-9en_US
dc.identifier.citationZhanel, G. G.; Golden, A. R.; Zelenitsky, S.; Wiebe, K.; Lawrence, C. K.; Adam, H. J.; Idowu, T.; Domalaon, R.; Schweizer, F.; Zhanel, M. A.; et al. Cefiderocol: A Siderophore Cephalosporin with Activity against Carbapenem-Resistant and Multidrug-Resistant Gram-Negative Bacilli. Drugs 2019, 79 (3), 271–289. https://doi.org/10.1007/s40265-019-1055-2en_US
dc.identifier.citationDomalaon, R.; Idowu, T.; Zhanel, G. G.; Schweizer, F. Antibiotic Hybrids: The Next Generation of Agents and Adjuvants against Gram-Negative Pathogens? Clin. Microbiol. Rev. 2018, 31 (2), e00077-17. https://doi.org/10.1128/CMR.00077-17en_US
dc.identifier.citationIdowu, T.; Schweizer, F. Ubiquitous Nature of Fluoroquinolones: The Oscillation between Antibacterial and Anticancer Activities. Antibiotics 2017, 6 (4), 26. https://doi.org/10.3390/antibiotics6040026en_US
dc.identifier.citationLyu, Y.; Yang, X.; Goswami, S.; Gorityala, B. K.; Idowu, T.; Domalaon, R.; Zhanel, G. G.; Shan, A.; Schweizer, F. Amphiphilic Tobramycin−lysine Conjugates Sensitize Multidrug Resistant Gram-Negative Bacteria to Rifampicin and Minocycline. J. Med. Chem. 2017, 60 (9), 3684–3702. https://doi.org/10.1021/acs.jmedchem.6b01742en_US
dc.identifier.citationIdowu, T.; Samadder, P.; Arthur, G.; Schweizer, F. Amphiphilic Modulation of Glycosylated Antitumor Ether Lipids Results in a Potent Triamino Scaffold against Epithelial Cancer Cell Lines and BT474 Cancer Stem Cells. J. Med. Chem. 2017, 60, 9724–9738. https://doi.org/10.1021/acs.jmedchem.7b01198en_US
dc.identifier.citationIdowu, T.; Samadder, P.; Arthur, G.; Schweizer, F. Design, Synthesis and Antitumor Properties of Glycosylated Antitumor Ether Lipid (GAEL)-Chlorambucil-Hybrids. Chem. Phys. Lipids 2016, 194, 139–148. https://doi.org/10.1016/j.chemphyslip.2015.07.003en_US
dc.identifier.urihttp://hdl.handle.net/1993/34092
dc.language.isoengen_US
dc.rightsopen accessen_US
dc.subjectAntimicrobial resistanceen_US
dc.subjectDrug discoveryen_US
dc.subjectAntimicrobial chemotherapyen_US
dc.subjectGram-negative bacteriaen_US
dc.subjectAntibioticsen_US
dc.subjectAntibacterial drug discoveryen_US
dc.subjectPseudomonas aeruginosaen_US
dc.subjectGalleria mellonellaen_US
dc.titleAminoglycoside-based antibiotic adjuvants: a platform for drug discoveryen_US
dc.typedoctoral thesisen_US
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