6-patrick_ch19_p3 other latams_1ec0c891d0b4778e18b3fd49ea06055c.pdf

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 19 ANTIBACTERIAL AGENTS Part 3: Other lactams ©1  Carbapenems Thienamycin Imipenem Meropenem Ertapenem Core structure of...

Patrick An Introduction to Medicinal Chemistry 3/e Chapter 19 ANTIBACTERIAL AGENTS Part 3: Other lactams ©1  Carbapenems Thienamycin Imipenem Meropenem Ertapenem Core structure of the carbapenem molecules Doripenem ©1 Newer β-Lactam Antibiotics Thienamycin (Merck 1976) (from Streptomyces cattleya) Acylamino side Opposite chain absent stereochemistry to penicillins OH Plays a role H Carbon in ß-lactamase H resistance H3C NH3 Hydroxyethyl side chain SS N O Double bond leading to CO2 high ring strain and an increase in -lactam ring reactivity Carbapenam nucleus Potent and wide range of activity vs. Gram +ve and Gram -ve bacteria Active vs. Pseudomonas aeruginosa Low toxicity High resistance to β-lactamases Poor stability in solution (ten times less stable than Pen G) ©1  Newer β-Lactam Antibiotics Thienamycin analogues used in the clinic aminomethylideneamino NH H OH HN H N-Formimidoyl derivative of Me S thienamycin N O 1. Produced by the bacteria Streptomyces CO2 cattleya. Imipenem 2. Broad spectrum of activity aerobic and anaerobic Gram positive as well as Gram negative bacteria. 3. It is particularly important for its activity against Pseudomonas aeruginosa and the Enterococcus species. 4. It is not active against methicillin- resistant Staphylococcus aureus Thienamycin (MRSA). ©1 Imipenem dehydropeptidase metabolites Cilastatin is a chemical compound which inhibits the human enzyme dehydropeptidase. Dehydropeptidase is an enzyme found in the kidney DHP= Dehydropeptidases Cilastatin ©1  Meropenem (Merrem) MEROTROL O H CH3 N C H OH H N Me H Me Me S N O CO2 pyrrolidin-2-yl-sulfanyl Carbapenam nucleus 1. Ultra-broad spectrum injectable antibiotic used to treat a wide variety of infections, including meningitis and pneumonia. 2. Penetrates well into many tissues and body fluids including the cerebrospinal fluid, bile, heart valves, lung, and peritoneal fluid ©1 Meropenem MEROTROL ©1  Ertapenem IV First-line treatment for community-acquired infections Effective against Gram negative bacteria. It is not active against MRSA, ampicillin-resistant enterococci, Pseudomonas aeruginosa or Acinetobacter species. Clinically useful activity against pyrrolidin-2-yl-sulfanyl anaerobic bacteria. ©1  Ertapenem A critical 1beta-methyl substituent shields the beta-lactam carbonyl group and serves to reduce dehydropeptidase (DHP)-1 catalyzed hydrolysis of the beta-lactam, enabling ertapenem to be administered without a DHP-1 inhibitor. A meta-substituted benzoic acid substituent increases the molecular weight and lipophilicity pyrrolidin-2-yl-sulfanyl of the molecule, and the carboxylic acid moiety, ionized at physiological pH, results in ertapenem having a net negative charge. As a result, ertapenem is highly protein bound and has an extended half-life, permitting a once-a-day treatment regimen. ©1 ©1 Doribax (Doripenem) ©1  Doripenem and Ertapenem (A) The structures of Doripenem and Ertapenem. (B) The chemical mechanism ©1 of hydrolysis of Ertapenem by the Mycobacterium tuberculosis BlaC. Stability toward dehydropeptidase ©1 Carbapenems ©1  Newer β-Lactam Antibiotics Monobactams Monocyclic β-Lactams: – Nocaridicin – Aztreonam Monobactams are β-lactam compounds wherein the β-lactam ring is alone and not fused to another ring, in contrast to most other β-lactams. They are effective only against aerobic Gram-negative bacteria Only commercially available monobactam antibiotic is aztreonam © Other examples of monobactams are tigemonam, nocardicin A, and tabtoxin 1  Newer β-Lactam Antibiotics Nocardicins (Fujisawa 1975) N OH HO2C O C D H H HC CH2 CH2 C N OH H2N O N Nocardicin A C O H CO2H Monocyclic -lactam ring - monobactams Moderately active in vitro vs narrow group of Gram -ve bacteria Active vs. Pseusomonas aeruginosa Inactive vs. Gram +ve bacteria Different spectrum of activity from penicillins Thought to operate by a different mechanism from penicillins Low toxicity ©1  Newer β-Lactam Antibiotics Clinically useful monobactam Me Me CO2H O N H Me N N H 2N S O Aztreonam N O SO3- Administered by intravenous injection Can be used for patients with allergies to penicillins and cephalosporins No activity vs. Gram +ve or anaerobic bacteria Active vs. Gram -ve aerobic bacteria ©1  β-Lactamase Inhibitors Clavulanic acid (Beechams 1976) (from Streptomyces clavuligerus) Sulphur replaced by O No acylamino O side chain H H H H 9 C N O OH S Me 4 6 5 R 3 7 1 N N 2 Me Acyl side H chain O O H CO2H CO2H Thiazolidine -Lactam -Lactam ring Oxazolidine ring ring Weak, unimportant antibacterial activity Powerful irreversible inhibitor of β-lactamases - suicide substrate Used as a sentry drug for Amoxicillin Augmentin = Amoxicillin + clavulanic acid Allows less Amoxicillin per dose and an increased activity spectrum Timentin = Ticarcillin + Clavulanic acid ©1 β-Lactamase Inhibitors Clavulanic acid - mechanism of action 1 2 NH 2 NH 2 O CH2OH N O CH2OH NH2 O HN O H Base H CO2H O CO2H HO OH OH O O 2-Amino-5-hydroxy-3-oxopentanoic acid 3 4 5 O CH2OH H2N NH NH NH CO2H H CH O CH2OH HC O HN O O O H CO2H O O Irreversibly blocked ©1 ©1 Avibactam (NXL104) non-β-lactam β-lactamase inhibitor Clavulanic acid NXL104 A new drug application for avibactam in combination with ceftazidime3ed (approved by the FDA on February 25, 2015), for treating complicated urinary tract (cUTI) and complicated intra- abdominal infections (cIAI) caused by antibiotic resistant-pathogens, including NXL104 those caused by multi-drug resistant Gram-negative bacterial pathogens ©1  β-Lactamase Inhibitors Penicillanic acid sulfone derivatives O O O O S S 1 Me Me 6 5 6 2 7 N N 3 N N 3 Me O O N CO2 Na CO2 Sulbactam Tazobactam Suicide substrates for -lactamase enzymes Sulbactam has a broader spectrum of activity vs -lactamases than clavulanic acid, but is less potent Unasyn = ampicillin + sulbactam Tazobactam has a broader spectrum of activity vs -lactamases than Clavulanic acid, and has similar potency Tazocin or Zosyn = piperacillin + tazobactam ©1  Olivanic Acids MM 13902 Naturally occurring carbapenem -lactamase inhibitors with antibacterial activity, produced by Streptomyces olivaceus (produced in low yield, isolation difficult) ©1  Other drugs which act on bacterial cell wall biosynthesis D-Cycloserine HO OH OH O O D-Ala-D-Ala H Ligase N O Racemase O H 3C NH2 X H 3C NH 2 X NH2 L-Alanine D-Alanine D-Alanine-D-Alanine D-4-amino-3-isoxazolidone Separated from Streptomyces garyphalu Acts at the cytoplasm It mimics the structure of D-Ala➔ Prevent formation of D-Ala-D-Ala Inhibits the enzyme L-Alanine Racemase and the D-Ala-D-Ala Ligase. (enzymes important in the cytosolic stages of peptidoglycan synthesis) responsible for linking the two d-alanine units together) ©1 Used in the treatment of tuberculosis Mechanism of action - bacterial cell wall synthesis NAM NAG NAM NAG SUGAR BACKBONE L-Ala L-Ala D-Glu D-Glu L-Lys Gly Gly Gly Gly Gly L-Lys Gly Gly Gly Gly Gly D-Ala D-Ala D-Ala D-Ala PENICILLIN TRANSPEPTIDASE D-Al ani ne NAM NAG NAM NAG SUGAR BACKBONE L-Ala L-Ala D-Glu D-Glu L-Lys Gly Gly Gly Gly Gly L-Lys Gly Gly Gly Gly Gly D-Ala D-Ala Cross linking ©1  Glycopeptides: VANCOMYCIN FAMILY Isolated Streptomyces orientalis Used in the prophylaxis and treatment of infections caused by Gram- positive bacteria (narrow-spectrum bactericidal glycopeptide)© 1  Crystal structure James R. Knox and R. F. Pratt in Antimicrobial Agents and Chemotherapy, Year 1990, Volume 34, Issue 7, Pages 1342-1347. The short peptide (L-Lysyl-D-Alanyl-D-Alanine), which is a bacterial cell wall precursor, bound to Vancomycin through five hydrogen bonds indicated by the dotted lines. ©1  VANCOMYCIN: Structure and Mechanism of Action Because vancomycin is a large molecule, it caps the tails and acts as a steric shield, blocking access to the transglycosidase and transpeptidase enzymes. Because vancomycin is such a large molecule, it is unable to cross the outer cell membrane of Gram -ve bacteria, lacks activity against those organisms. It is also unable to cross the inner cell membrane of Gram +ve bacteria, but this is not required as the construction of the cell wall takes place outside the cell membrane ©1  Capping Mechanism The transfer of a sugar residue from one glycoside to another (bond formation, particularly during polysaccharide synthesis) Transglycosylation ©1 Dimerization of VANCOMYCIN 5 H-Bonds 4 H-Bonds 5 H-Bonds ©1  VANOMYCIN: Biosynthesis Reactions involved in the biosynthesis of vancomycin. Vancomycin is derived biosynthetically from a linear heptapeptide containing five aromatic residues. These undergo oxidative coupling with each other to produce three cyclic moieties within the structure. Chlorination, hydroxylation, and the final addition of two sugar complete the structure 1 © units then  Resistance to VANCOMYCIN Modification of the pentapeptide chain leading to resistance Resistance has arisen from a modification of the cell wall precursors where the terminal d-alanine group in the pentapeptide chain has been replaced by d-lactic acid, resulting in a terminal ester link rather than an amide link. This removes one of the NH groups involved in the hydrogen bonding interaction with vancomycin. Vancomycin does not bind to D-Ala-D-Lac, which leads to vancomycin resistance ©1  Teicoplanins: Mixture of 5 major constituents and four minor (named Teicoplanin RS-1 through RS-5) β-D-glucosamine The teicoplanins belong to the vancomycin ©1 family but do not dimarize  Teicoplanin-A2-5 Its mechanism of action is to inhibit bacterial cell wall synthesis. Teicoplanin is marketed by Aventis under the trade name Targocid®. Teicoplanin A2-5 is used in the prophylaxis and treatment of serious infections caused by Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Enterococcus faecalis. ©1  Binding Mode of Teicoplanin Teicoplanins belong to the vancomycin family but do not dimarize. The long alkyl chain plays an important role is anchoring the antibiotic to the outer surface of the cell membrane where it is perfectly placed to interact with the building blocks for cell wall synthesis. Teicoplanin is used clinically for the treatment of Gram-positive infections and is less toxic than vancomycin. ©1 Eremomycin and LY33328 Semisynthetic glycopeptides New Glycopeptide Antibiotics LY33328 is 1000 times > active than vancomycin ©1  Bactericidal lipoglycopeptide for use in MRSA or other Gram-positive infections. Telavancin is a semi-synthetic derivative of vancomycin Semisynthetic glycopeptides Removal of a tetrahydropyran ring to leave an alcohol group (R4), modification of the hydrophobic tail (R2) and addition of a side chain with a phosphate group (R3), to give Telavancin , which was approved in 2009. ©1  Simplification of Natural Products Simplified analogues of the glycopeptides This lead compound: Capable of binding to D-Ala-D-Ala and D-Ala-D-Lac The complexity of the glycopeptides is an advantage in their targeting and selectivity, it is a problem when it comes to synthesizing analogues. Therefore, work has been carried out to try and prepare simplified analogues of vancomycin which are easier to synthesize, yet retain the desired selectivity. Structures such as those have been prepared which are capable of binding to d-Ala -d-Ala and d-Ala-d-Lac These now represent lead compounds for the development of future antibacterial agents ©1  There are another two mechanisms by which glycopeptides may have an antibacterial activity Firstly, it is possible that glycopeptide dimers disrupt the cell membrane structure. This is supported by the fact that glycopeptide antibacterial agents enhance the activity of aminoglycosides by increasing their absorption through the cell membrane. Secondly, RNA synthesis is known to be disrupted in the presence of glycopeptides. The possibility of three different mechanisms of action explains why bacteria are slow to acquire resistance to the glycopeptides. ©1  Bacitracin Bacitracin is Cyclic polypeptide complex produced Bacillus subtilis. Isolated in 1943 from a knee scrape from a girl named Margaret Tracy Binds to the lipid carrier responsible for transporting the NAM/pentapeptide unit across the cell membrane, thus preventing it from carrying out that role. Bacitracin interferes with the dephosphorylation of the C55- isoprenyl pyrophosphate, a molecule which carries the building blocks of the peptidoglycan bacterial cell wall outside of the inner membrane ©1 ©1  Summary β-Lactamase inhibitors are β-lactam structures that have negligible antibacterial activity but inhibit β-lactamases. They can be administered alongside penicillins to protect them from β-lactamases and to broaden their spectrum of activity. Carbapenems and monobactams are examples of other β-lactam structures with clinically useful antibacterial activity. Glycopeptides, such as vancomycin, bind to the building blocks for cell wall synthesis, preventing their incorporation into the cell wall. They also block the cross-linking reaction for those units already incorporated in the wall. The glycopeptides are the drugs of last resort against drug-resistant strains of bacteria. Bacitracin binds to and inhibits the carrier lipid responsible for carrying the cell wall components across the cell membrane. Cycloserine inhibits the synthesis of D-Ala-D-Ala. ©1