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Vectorisation of Gram-positive antibiotics into Gram-negative bacteria ECCMID Amsterdam, Netherlands 2019 S0331 Marvin J. Miller Department of Chemistry and Biochemistry University of Notre Dame Notre Dame, IN 46556, USA [email protected] eLibrary & Hsiri Therapeutics, LLC © by author The world is running out of antibiotics, WHO report confirms - 20 September 2017 IF YOU WEREN'T taking antibiotic resistance seriously before, now would be a good time to start. A project commissioned by the British government has released estimates of the near-future global toll of antibiotic resistance that are jaw-dropping in their seriousness and scale: 10 millions deaths per year, more than cancer, and at least $100 trillion in sacrificed gross national product. WHO Priority 1: CRITICAL AcinetobacterESCMIDbaumannii, carbapenem eLibrary-resistant Pseudomonas aeruginosa, carbapenem-resistant Enterobacteriaceae© by, carbapenem author-resistant • Changing membrane permeability via porin modification • Enzymatically deactivating the antibiotic (e. g. beta-lactamase) • Decreasing intracellular drug concentration by effluxESCMID pump systems eLibrary • Inadequate diagnostics Clatworthy, A. E. et. al.© Nature Chemical by biology 2007 author, 3, 541-548; Michael A. F., Walsh C. T. Science 2009, 325, 1089. • However, microbes still need to assimilate nutrients, especially IRON (Fe) • Bacteria need MICROMOLAR amounts of Fe to grow, multiply and sustain an infection • However, Fe is very insoluble & only 10-18 to ESCMID-24 eLibrary 10 molar free Fe is available in serum • How can bacteria assimilate enough Fe? Clatworthy, A. E. et. al.© Nature Chemical by biology 2007 author, 3, 541-548; Michael A. F., Walsh C. T. Science 2009, 325, 1089. Siderophores & Bacterial Fe(III) Acquisition Siderophore: multidentate Fe3+ chelator used by bacteria for extracellular solubilization of otherwise insoluble Fe3+ followed by protein-mediated active transport into cells. Siderophore-Mediated Iron(III) Transport Outer Membrane Receptors ESCMID eLibraryGram-negative Model 5 Sandy & Butler; Chem.© Rev. 2009by, 109, 4580. author Examples of Natural Siderophores Siderophores are multidentate Fe(III) chelators used by bacteria for extracelluar solubilization of otherwise insoluble Fe(III) followed by molecular recognition based protein-mediated active transport into cells. ESCMID eLibrary Hider, R. C.; Kong,© X. Chemistry by and Biology author of Siderophores. Nat. Prod. Rep. 2010, 27, 637-657. Siderophores for “Trojan Horse” Drug Delivery Sideromycins use the microbe’s iron acquisition system to smuggle a drug into the cell. (‘Trojan Horse’ approach) -Siderophore: Help to overcome the permeability problem by active transport. -Linker:ESCMID With or without drug release function. eLibrary -Drug: Activity may or may not be retained after attachment. Wencewicz, T. A.*; Miller, M. J. "Sideromycins as Pathogen-Targeted Antibiotics." in Topics in Medicinal Chemistry. 2017, Springer, Berlin, Heidelberg.© DOI: 10.1007/7355_2017_19by author “Controversy” – Can Sideromycins be Useful Antibiotics? Read the Old Literature – 1955 Effective Natural Sideromycins – in people! Albomycin, a new antibiotic, has been manufactured during O recent years by the pharmaceutical industry of the Soviet O O siderophore -linker- drug Union. It has been studied both in the laboratory and in N Fe Fe O N clinical practice, and it is the purpose of this paper to N O O HO summarize the results of the most important studies. OH O O H H N N N H N H HO Albomycin was obtained by Gause and Brazhnikova (1951) H O S H2N O from cultures of a new species of streptomycetes, O HN Y N CO2H Actinomycessuibtropicus. This antibiotic strongly inhibits H albomycins, OH Peptidase required the growth of Gram-positive cocci, chiefly pneumococcus natural siderophore for drug release or antibiotics no antibiotic activity and staphylococcus. More important, it inhibits the growth (V. Braun - Biometals 2008 of staphylococci resistant to other antibiotics, including G. Benz - series of papers 1980s) penicillin,ESCMID streptomycin, the tetracyclines, and erythromycin. eLibrary It is also effective against a number of Gram-negative bacteria. 1 mg of albomycin inhibits© the growthby of staphylococci author about ten times more strongly than an equal amount of penicillin. “Controversy” – Can Sideromycins be Useful Antibiotics? Read all the Relevant Literature Salmycins – natural amino glycoside sideromycins O O O siderophore -linker- drug N Fe Fe O N N O O Discovery & early report: Gause, G. F. British Medical HO OH O O H H Journal 1955, 1177- N N N In vivo efficacy: PEOPLE 1950s- H N H HO DiscoveryH : All of these compoundsO S are highly active H2N O Subsequent in vitro and in vivo studies: Braun, V. et al against StaphylococciO HN and Streptococci Y N CO2H Biometals. 2009, 22, 3-13. “The in vivo efficacy of at 0.01 µg/mL concentrations,H including resistant albomycins, OH Peptidase required albomycin … has been examined in a mouse (infection) nastrains.tural siderophore for drug release or antibiotics no antibiotic activity model. Albomycin is effective in clearing infections... Vertesy, L.; Aretz, W.; Fehlhaber(V., BraH.u-nW., - Bi oKoglermetals 2,0 08 The recovery rate of albomycin resistant mutants is Helv. Chim. Acta 1995, 78, 46-G60.. Benz - series of papers 1980s) lower thanESCMID that of the wild-type which suggests a eLibrary Synthetic studies: Roosenberg, J. M.; Dong, L.; reduced fitness of the mutants. Albomycin could be a Miller, M. J. J. Am. Chem. Soc. 2002, 124, 15001-05 useful antibiotic provided sufficient quantites can be In vivo efficacy: Braun, V. et al Biometals. 2009, 22, isolated ... or synthesized© chemically by” author3-13. Therapeutic Implications of Iron (Fe), Its Assimilation and Metabolism - the Creation of Designer Sideromycins Exploitation of microbial iron assimilation processes for development of new antimicrobial agents Key points: 1. Siderophore based molecular recognition 2. Linker considerations – releasable or not 3. Intracellular Drug target ESCMID eLibrary © by author Synthetic Sideromcyins - Imparting Microbe Selectivity by correct choice of conjugate components: Siderophore recognition Enterobactin as a xenosiderophore used by many Gram negative bacteria ESCMID eLibrary Zheng, T.; Bullock, J.© L.; Nolan, E.by M. J. Am. Chem. authorSoc., 2012, 134, 18388. Synthetic Sideromcyins - Imparting Microbe Selectivity by correct choice of conjugate components: Tripodal catechol ampicillin conjugate is selectively active against Pseudomonas ! COOH O O O N H Both conjugates 7 and 8 exhibited significantly N HN N S enhanced (>256-4000 fold) in vitro antibacterial H O activity against Gram-negative species compared to the parent drugs, especially against P. aeruginosa. R MIC in mM O NH O NH HN O 7 8 Ampicillin Amoxicillin OAc OAc AcO +Fe -Fe +Fe -Fe +Fe -Fe +Fe -Fe P. aeruginosa KW799/wt 33 0.05 25 0.05 >200 >200 >200 >200 OAc OAc AcO P. aeruginosa KW799/61 12.5 0.067 12.5 0.083 0.52 0.78 0.46 0.39 7 R=H ampicillin 8 R=OH amoxicillin P. aeruginosa PAO1 50 0.39 50 0.39 >200 >100 >200 >100 P. aeruginosa Pa4 25 0.39 25 0.21 >200 >100 >200 >100 P. aeruginosa Pa6 >200 >200 >200 >200 >200 >200 >200 >200 ESCMIDE. coli ATCC 25922 eLibrary150 1.56 100 6.25 16.7 12.5 4.17 4.17 K.pneumoniae ATCC >200 >100 >200 >100 >200 >100 100 >100 Ji, C. Miller, P. A.; Miller, M. J 8303 J. Am. Chem. Soc. 2012, ©134, 9898-9901 .by author Synthetic Sideromcyins - Results from Other Labs Verify the Iron Transport-Mediated Trojan Horse Concept ESCMID eLibrary Not all iron chelators are siderophores and one must consider proper iron binding© bystoichiometry author and molecular recognition Design, Syntheses & Studies of Sideromycins, Novel Antibiotics that Target Specific Infections – HT06 OH OH OH OH OH OH siderophore -linker- drug NHS/EDC Fe O O OH DMF/2-MeTHF OH HN HN O N O rt, 16 h N O Microbe Target Target OH O selectivity selectivity reactivity Bis-catechol core N (releasable 960 g O O or not) (PracticaChem) O NaHCO3,THF/H2O O O O H2N H2N NH NH H2N S NH S Ph Ph Ph N N Cl N O O O Cl CO2H CO2H Lorabid Ampicillin CO2H (carbacephem) Ceclor OH OH OH OH OH OH OH OH OH O O OH O OH HN OH HN N O HN N O O N O O H O H N H N NH N NH ESCMID eLibraryNH S O Ph S O Ph Sideromycin N Sideromycin O Ph Sideromycin N Cl YML-1-60 O Cl YML-1-62 N YML-1-109 O O CO H CO H HT-06 © byCO2H HTauthor-11 2 HT-07 2 ESCMID eLibrary © by author Design, Syntheses & Studies of Sideromycins, Novel Antibiotics that Target Specific Infections – HT06 HT-06 –IV Tolerability in ICR mice •Single IV dose tolerability from 25 mg/kg to 250 mg/kg •Two IV doses of 250 mg/kg – at zero time and 3.5 hours Results:ESCMID All doses up to 250 mg/kg eLibrary dosed once or twice were well tolerated with no observed adverse effect © by author Design, Syntheses & Studies of Sideromycins, Novel Antibiotics that Target Specific Infections – HT06 Effect of HT-06 on Mouse Survival (100% survival!) - IP Acinetobacter baumannii 17961 Sepsis Model 7 6 5 HT-06 250 mpk x 2 4 HT-06 50 mpk x 2 Ciprofloxacin 50 mpk x 2 3 Loracarbef 50 mpk x 2 Vehicle 2 Number of Mice of Number 1 0 Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 ESCMID• 6 to 8 week old female ICR mice eLibrary • IP inoculation with 108 CFU Acinetobacter baumannii ATCC 17961 • IV Rx at 30 min and 4 hrs • Rx - HT-06 250 mg/kg, HT-06 50 mg/kg, Ciprofloxacin 50 mg/kg, Loracarbef© 50 mg/kg, by Vehicle author Design, Syntheses & Studies of Sideromycins, Novel Antibiotics that Target Specific Infections – HT06 HT-06 (with/without sulbactam) vs.
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  • Synthetic Strategies to Combat Antibiotic Resistance

    Synthetic Strategies to Combat Antibiotic Resistance

    University of New Hampshire University of New Hampshire Scholars' Repository Master's Theses and Capstones Student Scholarship Winter 2018 Synthetic strategies to combat antibiotic resistance Jonathan Fifer University of New Hampshire, Durham Follow this and additional works at: https://scholars.unh.edu/thesis Recommended Citation Fifer, Jonathan, "Synthetic strategies to combat antibiotic resistance" (2018). Master's Theses and Capstones. 1262. https://scholars.unh.edu/thesis/1262 This Thesis is brought to you for free and open access by the Student Scholarship at University of New Hampshire Scholars' Repository. It has been accepted for inclusion in Master's Theses and Capstones by an authorized administrator of University of New Hampshire Scholars' Repository. For more information, please contact [email protected]. Synthetic strategies to combat antibiotic resistance BY Jonathan P. Fifer Chemistry (B.Sc), Penn State University, 2014 THESIS Submitted to the University of New Hampshire in Partial Fulfillment of the Requirements for the Degree of Master of Science In Chemistry December 2018 This thesis has been examined and approved in partial fulfillment of the requirements for the degree of Masters of Science in Chemistry. Synthetic strategies to combat antibiotic resistance BY Jonathan P. Fifer Thesis/Dissertation Director, Marc A. Boudreau, Assistant Professor of Chemistry ______________________________________ Eric B. Berda, Associate Professor of Chemistry ______________________________________ Arthur Greenburg, Professor of Chemistry ______________________________________ on December 12, 2018 Approval signatures are on file with the University of New Hampshire Graduate School. ii -TABLE OF CONTENTS- Dedication ………………………………….…………………………….……………….. iv Acknowledgements ………………………………………………………..……………… v List of Schemes …………………………………………………………….…………….. vi - vii Lists of Figures and Tables …………………….……..…………………………….……. viii Abbreviations ….……………..…………….…………………………………..………… ix - xi Abstract ………………………………………………………………………...………… xii - xiii Chapters 1.