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Mechanistic Classes of Antibacterials Benjamin D. Horning Group Meeting November 30, 2011 http://images.agoramedia.com/cs/eh/cs_diarrhea_antibiotics_causing_diarrhea_article.jpg http://www.irishhealth.com/content/image/853/Image1.jpg Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003 Antibacterials- A Subclass of Antibiotics An antibiotic is “a chemical substance having the capacity, in dilute solution, to kill or inhibit growth of microorganisms.” This definition includes antifungals and antiprotozoals. Antibiotics travel inside the body to fight microorganisms, antiseptics are used externally, and disinfectants are for non-living surfaces. antimicrobials antibiotics disinfectants antiseptics antibacterials antifungals antiprotozoals applied to nonliving objects for external applications to living organisms for internal or external use kill fungus kill protozoans (single-celled eukaryotes) http://www.lysol.com/images/products/no-mess-automatic-toiletbowl-cleaner.png, http://www.couponmamacentral.org/wp-content/uploads/2011/09/purell.jpg, http://www.medexpressrx.com/blog/wp-content/uploads/2010/07/antibiotics4.jpg, http://drugster.info/drug/medicament/22969/, http://modernmedicalguide.com/wp-content/uploads/2010/03/Antiprotozoal-Drugs.jpg Antibacterials- A Subclass of Antibiotics human antibacterials in vitro antibacterials S. pyogenes veterinary and feedstock antibacterials S. mutans S. pneumoniae Streptococcus pyogenes - strep throat, rheumatic fever, scarlet fever, necrotizing fasciitis Streptococcus pneumoniae - (bacterial) pneumonia Streptococcus agalactiae - meningitis, (bacterial) pneumonia Escherichia coli - gastroenteritis, urinary tract infections, sepsis, diarrhea (Methicillin-resistant) Staphylococcus aureus (MRSA) - Imepetigo, Staph infections, toxic shock syndrome Image from: http://inst.bact.wisc.edu/inst/images/book_3/chapter_13/13-3.jpg http://www.webcitation.org/5uJyti0mG http://www.medicinenet.com/sepsis/page4.htm Top-Selling Antibiotics in the USA O 21 F CO2H N Me N 54 Me N Me N H Me 94 Me OH Me OH Levaquin (Levofloxacin) O OH Me Me N OH H OH NH2 O O OH O CO2H OH O O Medicis $673 Million O 125 OH Doryx (Doxycycline) Medicis $673 Million O F OH Solodyn (Minocycline) Ortho-McNeil $1,355 Million F CO2H O 126 F H CO2H H N HN N N N N HN OMe H H Avelox (Moxifloxacin) Ciprodex otic (Cipro and Dexamethasone) Merck $353 Million 138 N 160 O Me O Zyvox (Linezolid) Pfizer $223 Million Alcon $253 Million OH 166 OH O O O Cl HO H O H N N O H H O N H H HO O HO OH O O Me H N HO Me H3N HO F Vigamox (Moxifloxacin) Alcon $255 Million O N N HN OMe O H NH2 N O 97 Me H O Me H Me Me N OH H Cl O N H O N O H OH Me O N H OH Me NHMe NH2 NH2 OH O OH OH O O Oracea (Doxycycline) OH Vancocin (Vancomycin) ViroPharma $192 Million Galderma $187 Million http://cbc.arizona.edu/njardarson/group/top-pharmaceuticals-poster Antibiotics- Why You Should Care of 57 million annual deaths Vaccinations and antibiotics can cure or prevent the majority of infectious diseases currently afflicting humanity. Antibiotic use introduces evolutionary selection pressure to bacteria; Resistant strains are selected for, and cause antibiotics to become ineffective. Bacterial resistance has been observed for every class of antibiotic introduced, sometimes within one year. New therapies will be needed. Graph from: Morens, D. M.; Folkers, G. K.; Fauci, A. S. Nature 2004, 430, 242-249 Table from: Palumbi, S. R. Science 2001, 293, 1786-1790 Strategies to Slow the Development of Antibiotic Resistance 108 bacteria 107 one error per bases 10 mutants (~0.3% of genes) antibiotic treatment 1 bacterium selection for resistant bacteria bacterial growth 108 bacteria completely resistant Overkill (multiple antibiotics) has worked well for HIV/AIDS, but not always applicable for bacteria (side effects). Direct observation therapy - continue antibiotic dose until no bacteria remain (not practical). Use narrow-spectrum antibiotics when applicable. Withhold the most powerful drugs - prevented vancomycin resistance for >30 years - difficult business model for pharma. Continue to develop new therapies and improve old therapies. Palumbi, S. R. Science 2001, 293, 1786-1790 Bacterial Resistance - Three Flavors Three types of bacterial resistance to antibiotics have been observed, coming either from random mutation under the selection pressure of antibiotics, or from antibiotic-producing bacteria. Resistance can be spread amongst bacteria via horizontal gene transfer. NH2 N N O H N Ph S O N O Me Me N O N O OH CO2H H2O RlmN Cfr !-lactamase NH2 Ph N O S OH N Me NH O HN N Me O Me N Me O CO2H O export pumps (efflux) antibiotic modification (only natural products and semisynthetics) OH enzymatic target modification http://www.sciencephoto.com/image/151999/530wm/C0089313-Active_efflux,_artwork-SPL.jpg Fujimori, D. G. et. al. J. Am. Chem. Soc. 2010, 132, 3953-3964 Paul Ehrlich and Drug Discovery Made seminial contributions in histology, haematology, immunology, oncology, microbiology and pharmacology. Alongside Ilya Mechnikov, won the Nobel Prize in Physiology or Medicine in 1908 “in recognition of their work on immunity.” Most famous for his discovery of Salvarsan (arsphenamine, #606), a compound for the treatment of syphilis, which was discovered during the first screen of a library of compounds for pharmaceutical activity, and later part of the first optimization of a lead, becoming the first blockbuster drug and presaging modern drug discovery. H2N HO OH HO H2N NH2 Paul Ehrlich and Sahachiro Hata Frankfurt 1910 As As As As As NH2 As As As As As OH OH HO NH2 HO NH2 H2N HO NH2 NH2 NH2 Revised structure of Salvarsan OH OH Bosch, F.; Rosich, L. Pharmacology 2008, 82, 171-179 www.nobelprize.org/nobel_prizes/medicine/laureates/1908/ Salvarsan http://pubs.acs.org/cen/coverstory/83/8325/8325salvarsan.html Lloyd, N. C.; Morgan, H. W.; Nicholson, B. K.; Ronimus, R. S. Angew. Chem. Int. Ed. 2005, 44, 941-944 The Four Major Targets of Antibiotics Walsh, C. T. Nature Reviews Microbiology 2003, 1, 65-70 Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003 The Four Major Targets of Antibiotics Antibiotics either target processes that are unique to bacteria - cell wall biosynthesis and folate metabolism - or processes that have different enough machinery to allow selective inhibition of bacterial over human versions - protein biosynthesis and DNA and RNA replication and repair. O O NH2 S S NH2 O H2N Sulfanilamide - 1936 S O N H2N O NH2 O N Prontosil - 1932 H N Sulfacetamide S CO2H HN H2N N N H N H HO2C O H N Me O O Me H2N O O H N N O H2N Sulfamethoxazole N H Tetrahydrofolic acid NH2 OMe N H2N N OMe OMe Trimethoprim - 1940s Walsh, C. T. Nature Reviews Microbiology 2003, 1, 65-70 Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003 Antibacterials Inhibiting Bacterial Folate Biosynthesis Prontosil was the first sulfa drug, discovered by Gerhard Domagk while working for Bayer AG. O Bayer AG hoped to use its expertise in dyes to develop a Ehrlich-style “magic bullet” dye that could be selective for pathogenic bacteria, found Prontosil. Immensely successful as the first broad-spectrum antibiotic. O N H2N NH2 S NH2 N Prontosil - 1932 Bayer AG’s revenue stream was undercut when a team of French scientists found that Prontosil is a prodrug, and becomes sulfanilamide in the body, the patent for which had long ago expired. in vivo metabolism O S Gerhard Domagk Nobel Prize 1939 “for the discovery of the antibacterial effects of prontosil” Massive product and marketing of sulfanilamide followed; One preparation, called Elixir Sulfanilamide, was a solution in ethylene glycol. This raspberry-flavored concoction caused over 100 deaths in 1937. NH2 O In 1938, the FDA passed the Federal Food, Drug and Cosmetic Act, requiring safety tests for a variety of product. This is why we do clinical trials for all new medicines today. H2N Sulfanilamide - 1936 http://www.nobelprize.org/nobel_prizes/medicine/laureates/1939/domagk.html# http://www.fda.gov/AboutFDA/WhatWeDo/History/ProductRegulation/SulfanilamideDisaster/default.htm for a history of clinical trials, see: http://blogs.scientificamerican.com/guest-blog/2011/10/06/molecules-to-medicine-clinical-trials-for-beginners/ Sulfa Drugs - Tetrahydrofolate Biosynthesis in Bacteria O N HN H2N O O O O P P P O- O O- O OH N N H para-amino benzoate H2N N HN CO2H H2N O O- O O P O- OH H N O S N N H Me O H2N 7,8-Dihydropteroate Synthase 7,8-Dihydropteroate Synthase H N O CO2H O N HN H2N N S O N H H2N N HN H2N N N H 7,8-Dihydrofolate O CO2H N H N H N H 7,8-Dihydropteroate O N N O N H 7,8-Dihydropteroate O Me O N HN N H N O O NADPH HN HO2C H2N N H N CO2H N H N H HO2C N H 5,6,7,8-Tetrahydrofolate Sulfa Drugs - Tetrahydrofolate Biosynthesis in Bacteria O O N HN H2N O O P P O- O O- O OH S N H HN H2N N NH2 N H H2N N H 7,8-Dihydropteroate HN N H H2N N N H O P O- OH H N O Me O O N O H2N 7,8-Dihydropteroate Synthase H N O S Me George H. O Hitchings N O Nobel Prize 1988 HN N H “for their discoveries of N OMe important principles for H2N N N OMe H drug treatment” 7,8-Dihydropteroate Trimethoprim OMe N O CO2H O N O- S combination marketed as co-trimoxazole N O N H CO2H N O O H2N N N Sulfamethoxazole 7,8-Dihydropteroate Synthase O Me P H2N para-amino benzoate H2N O O N O HN CO2H N H N O O NADPH HN HO2C H2N N H 7,8-Dihydrofolate N CO2H N H H N N H HO2C N H 5,6,7,8-Tetrahydrofolate Success and Failure with Bacterial Metabolite Biosynthesis OH O OH O Me O OH platensymicin O O Me n O HN OH n Me n fatty acid biosynthesis N H H2N O N H N CO2H N H N H HO2C N H Folate is an essential nutrient for humans, they cannot synthesize it. Bacteria must synthesize folate, and cannot obtain it from their environment. Zlitni, S. and Brown, E. D. Nature 2009, 458, 39-40 Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003 The Four Major Targets of Antibiotics H N Ph S O Me Penicillin G Me N O CO2H Me N O H N S S N O CO2H HO H N O H O HO O O O Cl O O Cl HO HO OH O Me H N O O H N H O H H N H OH OH Me O O Me N N H O OH Cefepime (cephalosporin) OH Me H3N HO N+ N O H2N H H NHMe NH2 Vancomycin (peptidoglycan) Antibacterials that Target Cell-Wall Biosynthesis Images from: http://fernness.com/science-01.html Antibacterials that Target Cell-Wall Biosynthesis Transglycosylases MurG MurB MurC Transpeptidase β-lactams MurD MurF Cell wall allows cells to survive in hypotonic media, where other wise swelling of the cell would cause it to burst. Murein , greek word for wall, enzyme called MurAG The cell wall is called murein, from the greek word for wall, and the enzymes involved in its construction are hence named MurA, MurB, etc. Images from: Höltje, J.-V. Microbiol. Mol. Biol. Rev. 1998, 62, 181-203 β-Lactams: Penicillins, Cephalosporins and Carbapenems H OH Me O H OH H O O H HN H O O NHAc HO H H NHAc Me H O H OH H O O O HN O NH HO2C NHAc H O Me O H O O Me NH O -D-Ala TPase O NH O NH2 NH HO2C O CO2H Me NH NH O CO2H O NH2 HN HO2C NH O HO2C Me O N H -TPase O R NH Me S O NH O Me TPase O NH S Me CO2H NH O Ph OH N O O Me H N Ph NH O Me O TPase HN CO2H O N H O NH Me H Me CO2H Covalent intermediates have half-lives from several hours to many days Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003, p. 39 Discovery of Penicillin: Nobel Prize1945 Sir Alexander Fleming Sir Howard Florey "for the discovery of penicillin and its curative effect in various infectious diseases" Dr. Ernst B. Chain assisted by Sir. Robert Robinson http://www.nobelprize.org/nobel_prizes/medicine/laureates/1945/ β-Lactams: Penicillins, Cephalosporins and Carbapenems H N Ph S O N Me N O R CO2H Penicillin G (penicillin) Me N S Me thiazolidine O H N S S S N O N+ N R O H2N N CO2H Cefepime (cephalosporin) HO NH2 H Me N O dihyrothiazine S CO2H Thienamycin (carbapenem) N R dihydropyrrole Structural modifications allow decreases susceptibility to β-lactamases. β-Lactams: Resistance Mechanisms - β-Lactamases Costs of over $30 billion per year due to β-lactamase-mediated resistance Ph NH O H N Ph Ph S O !-lactamase Me H2O Me N O Enz S O H2O Me Me HN O NH O O S OH Me HN CO2H CO2H Me CO2H OH inactive Enz Me N S O H2N H N S S N O N N N+ O H2N OH NH N O O Me H2O !-lactamase Me O CO2H S O Enz HN H2O Me slower N+ CO2H Enz larger side chain slows hydrolysis by occluding water from the active site Statistics from: Palumbi, S. R. Science 2001, 293, 1786-1790 β-Lactams: Resistance Mechanisms - β-Lactamase Inhibitors HO Clavulanic acid (right) shows minimal activity against transpeptidases (penicillin-binding proteins) but is highly active against β-lactamases. N A combination of Clavulanate and Amoxicillin is marketed by GlaxoSmithKline as Augmentin (and by Pfizer as Clavamox) O O O CO2H HO HO !-lactamase N O O Enz HO O O HN O H+ Enz O+ HN O CO2H CO2H CO2H OH Enz Nuc Enz Nuc O Enz O H Enz Nuc O O Enz O +H Enz O 2N Enz CO2H OH O O +HN H+ CO2H OH Statistics from: Palumbi, S. R. Science 2001, 293, 1786-1790 Aminoglycosides:Vancomycin and Teicoplanin HO Me H3N HO H N O H O HO O H N O O H N H O H H N H H H Me O HO HO Me O NH2 N H O N H H N O O HN NH2 HN HO2C O HO OH O H N NH O NHMe O Cl O O N N H O OH OH Me O O Cl O OH O OH O O Cl Cl HO HO O N H Me O O Me Me OH O OH OH O OH HO O HO OH OH O HO OH OH vancomycin “The antibiotic of last resort” Discovered in soil sample from Borneo, isolated by Eli Lilly chemist Edmund Kornfeld >30 years before resistance observed (1953 to 1987) teicoplanin Marketed by Sanofi-Adventis Approved in 2009 Chen, L.; Walker, D.; Sun, B.; Hu, Yanan; Walker, S.; Kahne, D. Proc. Nat. Acad. Sci. 2003, 100, 5658-5863 Aminoglycosides:Vancomycin and Teicoplanin Aminoglycosides:Vancomycin Resistance HO H3N Me H H N H Me O H N H Me N N H H O OH OH Me O O H HO NH2 R H N Me H H N H O OH N N H H H Me NH NH2 Me R O O N H O Me O Me O N H Me OH O O H OH Me O O O O O N O H N H O HO OH O H Cl O O H N O Me O Cl HO NH O O O H N H O HO HO O OH O Cl O O H N O HO O Cl HO H3N O O OH Me OH O HO HO OH Me Removing this single hydrogen-bond interaction reduces vancomycin affinity for the terminal dipeptide by 1,000-fold. Replacing the terminal D-Ala with D-Ser reduces affinity by 6-fold Aminoglycosides:Vancomycin Resistance HO H3N Me H N O HO H O HO O O H N O HO H O H Me H N H H R NH2 Me N H H Me H Me HO H H N O O H H H OH R N+ H H N H OH Me O O O H N N N H H O Me H Me NH NH2 OH Me O O Me Cl O O N O H N O NH O Cl HO O HO OH O N N H O OH OH Me O O O O O O H N OH O Cl Cl HO H3N O O OH Me OH O HO HO OH Me N H O O O O Me Removing this single hydrogen-bond interaction reduces vancomycin affinity for the terminal dipeptide by 1,000-fold. Replacing the terminal D-Ala with D-Ser reduces affinity by 6-fold Boger, 2011 showed that activity can be returned by replacing the amide with an amidine Xie, J.; Pierce, J. G.; James, R. C.; Okano, A.; Boger, D. L. J. Am. Chem. Soc. 2011, 133, 13946-13947 The Four Major Targets of Antibiotics O Me Me HO OH Me Et HO O O O O Me OH NMe2 O O Me O N O H N F OMe O N Me O Me OH Me Erythromycin (Macrolide) Linezolid (Oxazolidinone) OH Me H N H Me OH NH2 OH O OH OH O O Tetracycline Antibiotics Blocking Bacterial Protein Biosynthesis transcription DNA translation RNA Me protein Figure from: Steitz, T. A. Nat. Rev. Mol. Cell Biol. 2008, 9, 242-253 Antibiotics Blocking Protein Biosynthesis: Erythromycin O Me O Me HO Me OH Me Et HO Me OH HO O O NMe2 O Me N Me Et O OH N OMe O Me O Erythromycin Me OH Me O OH O Me Me Et O Me N Me OH O Me O OH Me N O Me HO O NMe2 O Me OH Me O O Me Erythronolide (Erythromycin aglycone) Telithromycin First isolated by Eli Lilly Scientist J. M. McGuire from soil samples collected by A. Aguilar which contained Saccharopolyspora erythraea, a species of actinomycete (major group of antibacterial-producing bacteria) Acid-instability hampered widespread application of early derivatives; Mono-deglycosylation, C-6 methylation and carbamate introduction aided in newer generations. First total synthesis: Woodward, R. B. et. al. J. Am. Chem. Soc., 1981, 103, 3210–3213 Erythromycin Binds to the Ribosome Exit Tunnel Image from: http://www.weizmann.ac.il/sb/faculty_pages/Yonath/10A-1.jpg Figure from: Schlünzen, F. et. al. Nature 2001, 413, 814-821 Antibiotics Blocking Protein Biosynthesis: Erythromycin dimethylation or adenosine replacement causes resistance - humans have guanosine Colored lines indicate groups that are <4.4 Å apart Figure from: Schlünzen, F. et. al. Nature 2001, 413, 814-821 Erythromycin Resistance in Bacteria O Me O Me Me OH Et Me O O Me O OleI Me O OMe O Me Me O OR2 OMe O Me Me OH Me O Me OH Et OR1 O Me OH O Me OleB NMe2 HO O R1= O Me HO R2= O Me O Me Me OH Et Me O O Me O OleR OMe O Me O Me OH Me O Me O NMe2 O Me Me OH Et OR1 O OH O O O Me HO HO OR2 OMe O Me O Me OH Me Adapted from: Quiros, L. M. et. al. Mol. Microbiol. 1998, 28, 1177-1185 Antibiotics Blocking Protein Biosynthesis: Linezolid (Zyvox) O O N N O H N F Me O Linzeolild (Zyvox) Pfizer, $223 million in 2010 Antibacterial effects of oxazolidinone originally discovered by DuPont, abandoned due to toxicity issues. Pharmacia/Upjohn later salvaged the product and (after being incorporated by Pfizer) released Zyvox in 2000. To date, Zyvox is the only oxazolidinone clinically approved, but many others are currently in clinical trials Represents the first widely-used novel antibiotic structural class since the 1960s (fluoroquinolones) Differences in binding site between other protein biosynthesis inhibitors prevents cross-resistance Structure from: Ippolito, J. A. et. al. J. Med. Chem. 2008, 50, 3353-3356 Antibiotics Blocking Protein Biosynthesis: Tetracycline O O N N O H N F Me O O Me Me HO OH Me Et Macrolides and oxazolidinones interact with the 50S ribosomal subunit Me OH NMe2 HO O O O O OMe O Me Me OH O OH Tetracyclines interact with the 30S ribosomal subunit Me Me Me H H N Me OH NH2 OH O OH OH O O Figure from: Williamson, J. R. Nature 2000, 407, 306-307 Antibiotics Blocking Protein Biosynthesis: Tetracycline Cl HO Me H Me N Me H Me Me N HO Me OH H H OH OH OH NH2 OH O OH OH O Me H H N Me OH NH2 O OH chlorotetracycline (aureomycin) O OH OH NH2 O O OH O OH OH O O tetracycline (acromycin) oxytetracycline (terramycin) Chlorotetracycline (aureomycin) was the first tetracycline antibiotic, discovered in a soil sample in 1948 (again biosynthesized by actinomycetes) Oxyotetracycline (terramycin) was subsequently discovered in 1949 by a nascent Pfizer, and was the subject of the first mass-marketing drug campaign. This drug put Pfizer on the map. R. B. Woodward and Pfizer collaborated to solve the structure of terramycin, mostly succeeding (mis-assigned one stereocenter) Hydrogenation of aureomycin gave the deschloro product, which maintained activity, and was one of the first semi-synthetic antibiotics. Baran group meeting on Tetracyclines (http://www.scripps.edu/chem/baran/html/meetingschedule.html) Chopra, I.; Roberts, M. Microbiol. Mol. Biol. Rev. 2001, 65, 232-260 Novel Tetracyclines from Tetraphase Me F H H N OH O N N H Me NH2 OH O OH OH O O TP-434 Andrew G. Myers Profssor of Chemistry Harvard University Fully synthetic tetracyclines overcome bacterial resistance problems in ways that semisynthetics are unable to. Business plan includes developing new broad spectrum antibiotics as well as narrow-spectrum inhibitors. http://tphase.com/ Antibiotics Interfering with DNA Replication and Transcription OH OH Me Me HO O O Me O Me Me O Novobiocin O OH H2N H N O O O F CO2H Me N CO2H N N N HN Me Nalidixic acid Ciprofloxacin O O F F CO2H CO2H H N N N Me O N HN N OMe Me H Levofloxacin Moxifloxacin Fluoroquinolones Affecting DNA Replication and Transcription O CO2H Me N Nalidixic acid was the first synthetic quinolone antibiotic, formed as a byproduct during chloroquine (anti-malarial) manufacture in the early 1960s. N Me Nalidixic acid O F Ciprofloxacin, or Cipro, is a second-generation fluoroquinolone, patented in 1983 by Bayer A. G. and receiving FDA approval in 1987. Fluorine substitution at the 6-position (common by this point) provides activity against both gramnegative as well as gram-positive bacteria. Sales were $242 million in 2008. CO2H N N HN Ciprofloxacin O O F CO2H F CO2H H N Me N N O Levofloxacin N HN Me N OMe Levofloxacin (Levaquin or Tavanic) and Moxifloxacin (Avelox or Avelon) are fourthgeneration fluoroquinolones, generating $1,355 and $353 million in revenues in 2010, respectively. H Moxifloxacin Emmerson, A. M.; Jones, A. M. J. Antimicrob. Chemother. 2003, 51, Suppl. S1, 13-20 DNA Replication and Repair Causes Supercoiling www.benthamscience.com/cmcaca/sample/cmcaca1-1/holden/f3-p7holden.gif open.jorum.ac.uk/xmlui/bitstream/handle/123456789/956/Items/S377_1_013i.jpg Quinolones Stabilize the DNA-Gyrase Covalent Intermediate Quinolones (and coumarins) cause accumulation of the doubly-cut covalent DNA-gyrase intermediate. The nature of the binding is uncertain (resistance hotspots on gyrA and parC subunits, may bind altered conformation of DNA) Tyr122 Tyr122 O OH OH 5' 3' A T C G A T C G A T C G A T C G T A G C T A G C T A G C T A G C 3' 5' 5' 3' O A T C G A T T A G C T A G C T A -O O HO Tyr122 F O CO2H R N R P O P O O- C G A T C G A T C G G C T A G C 3' 5' OH O Tyr122 R Pan, X.-S.; Fisher, L. M. J. Antimicrob. Agents Chemother. 1997, 41 (2), 471-474 Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003 pp. 71-77 Future Directions of Antibiotics Research - Molecules Synthetic (top) and natural-product derived (left) antibiotics that have been launched since 2000 PA-824 is a tuberculosis antibiotic, the processscale synthesis of which was developed at Princeton University Marsini, M. A.; Reider, P. J.; Sorensen, E. J. J. Org. Chem. 2010, 75, 7479-7482; Butler, M. S.; Cooper, M. A. The Journal of Antibiotics 2011, 64, 413-425 Future Directions of Antibiotics Research - Molecules Molecules currently in phase III clinical trials Butler, M. S.; Cooper, M. A. The Journal of Antibiotics 2011, 64, 413-425 Future Directions of Antibiotics Research - Targets Fatty acid biosynthesis - works well for antiseptics, unlikely to be applicable for antibacterials (environmental uptake). Two-component signal transduction - unique bacterial system to modify behavior based on external stimuli. O CoA n Me S OH n O CoA S O Me n O OH Efflux blockers - Target specific, not general. Quorum sensing Oxidative stress repair Walsh, C. T. Antibiotics: Actions, Origins, Resistance, American Society for Microbiology Press, Washington DC, 2003, chapter 15 Quorum Sensing as a Novel Antibacterial Target Two strategies may be possible to use quorum sensing as an antibacterial strategy: Develop molecules that turn on QS-regulated genes early, allowing the immune response to eliminate the now-revealed intruder. Develop antagonists that prevent QS-regulated genes from being turned on, preventing virulence. Bonnie Bassler Princeton University check out TED talk! www.ted.com/talks/bonnie_bassler_on_how_bacteria_communicate.html http://upload.wikimedia.org/wikipedia/commons/c/cf/Quorum_sensing_diagram.png http://www.advancedhealing.com/blog/wp-content/uploads/2009/12/Quorum_Sensing_Biofilm_Formation.gif Quinolones Stabilize the DNA-Gyrase Covalent Intermediate Studies non-linear effects in systems biology In 2007, showed that all bactericidal antibiotics kill bacteria by a common mechanism, oxidative damage from hydroxyl radicals James J. Collins Suggests targeting RecA in order to potentiate current antibiotic therapies Professor of biomedical engineering at Boston University RecA - involved in DNA repair Inhibitors currently being developed by Scott Singleton, professor at UNC Collins, J. J. et. al. Cell. 2007, 130, 797-810 Wigle, T. J.; Singleton, S. F. Bioorg. Med. Chem. Lett. 17 (12): 3249–53. Nitric Oxide as Antibiotic Protection for Bacteria NH2+ H2N NH HO2C NH2 L-Lysine NADPH + O2 Evgeny Nudler Professor of Biochemistry NYU Langone Medical Center H2N N OH NH HO2C NH2 NADPH + O2 H2N O NH HO2C NH2 L-Citrulline N O Also H2S! Nitric Oxide Synthase Nudler, E. A. et. al. Science 2009, 325, 1380-1384; Nudler, E. A. et. al. Science 2011, 334, 986-990 http://mycrains.crainsnewyork.com/40under40/profile_images/2008/photogallery/2008NudlerLevgeny_3.jpg Fin