b-Lactamase Inhibitors Clavulanic acid (Beecham 1976)(from Streptomyces clavuligerus) Sulphur replaced by O No acylamino side chain H 9 O 5 6 7 N 1 OH 4 3 2 H O H CO2H b-Lactam Oxazolidine ring • • • • • • Weak, unimportant antibacterial activity Powerful irreversible inhibitor of b-lactamases - suicide substrate Used as a sentry drug for ampicillin Augmentin = amoxicillin+ clavulanic acid Allows less amoxicillin per dose and an increased activity spectrum Timentin = ticarcillin + clavulanic acid b-Lactamase Inhibitors Augmentin = Amoxicillin + Clavulanic Acid b-Lactamase Inhibitors Penicillanic acid sulfone derivatives O S O 6 5 7 N • • • S Me 1 Me 3 CO2 Na O 6 2 Sulbactam • • O O N Me N 3 N O N CO2 Tazobactam Suicide substrates for b-lactamase enzymes Sulbactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, but is less potent Unasyn = ampicillin + sulbactam Tazobactam has a broader spectrum of activity vs b-lactamases than clavulanic acid, and has similar potency Tazocin or Zosyn = piperacillin + tazobactam The aminopenicillins + b-lactamase inhibitor combinations include ampicillinsulbactam (parenteral) and amoxicillin-clavulanate (oral) Gram-positive bacteria Some Staphylococcus aureus, Streptococcus pyogenes, Viridans streptococci, Some Streptoocus pneumoniae, Some enterococci Listeria monocytogenes Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Many Enterobacteriaceae Anaerobic bacteria Clostridia spp. (except C. difficile), Actinomyces israellii, Bacteroides spp. Spirochetes Borrelia burgdorferi Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins Class 2 - CO2H at the a-position (carboxypenicillins) Examples CO2R CH C H N H H S O Me R=H R = Ph CARBENICILLIN CARFECILLIN Me N O CO2H • • • • • • • • Carfecillin = prodrug for carbenicillin Active over a wider range of Gram -ve bacteria than ampicillin Active vs. Pseudomonas aeruginosa Resistant to most b-lactamases Less active vs Gram + bacteria (note the hydrophilic group) Acid sensitive and must be injected Stereochemistry at the a-position is important CO2H at the a-position is ionised at blood pH Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins Class 2 - CO2H at a-position (carboxypenicillins) Examples CO2H S H H N O H N O S Me TICARCILLIN Me CO2H • • • • • • Administered by injection Identical antibacterial spectrum to carbenicillin Smaller doses required compared to carbenicillin More effective against P. aeruginosa Fewer side effects Can be administered with clavulanic acid Problem 3 - Range of Activity Examples of Broad Spectrum Penicillins Class 3 - Urea group at the a-position (ureidopenicillins) Examples O Azlocillin Mezlocillin HN MeO2S N O N O R2N NH N H H N O Piperacillin • • • • • • Et N N O O H N O S Me Me CO2H Administered by injection Generally more active than carboxypenicillins vs. streptococci and Haemophilus species Generally have similar activity vs Gram - aerobic rods Generally more active vs other Gram - bacteria Azlocillin is effective vs P. aeruginosa Piperacillin can be administered alongside tazobactam The Extended Spectrum Penicillins include Piperacillin and Ticarcillin (parenteral) as well as Carbenicillin (oral) Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Gram-negative bacteria Neisseria meningitidis, Some Haemophilus influenzae, Some Enterobacteriaceae, Pseudomonas aeruginosa Anaerobic bacteria Clostridia spp. (except C. difficile), Some Bacteroides spp. Extended-Spectrum Penicillin + b-Lactamase Inhibitor Combinations include:Piperacillin-tazobactam as well as ticarcillin-clavulanate (both pairs are parenteral) Gram-positive bacteria Some Staphylococcus aureus, Streptocosoccus pyogenes, Viridans streptococci, Some Streptococcus pneumoniae, Some enterococci Listeria monocytogenes Gram-negative bacteria Neisseria spp. Haemophilus influenzae, Most Enterobacteriaceae, Pseudomonas aeruginosa Anaerobic bacteria Clostridia spp. (except C. difficile), Bacteroides spp. CEPHALOSPORINS O R C H N H H S N OAc O CO2H 1. Introduction • Antibacterial agents which inhibit bacterial cell wall synthesis • Discovered from a fungal colony in Sardinian sewer water (1948) • Cephalosporin C identified in 1961 Giussepe Brotzu noticed that the substance cultured from the sewer water had activity against Salmonella typhi, the active cause of typhoid fever Typhoid fever is transmitted human to human by contact with contaminated feces. 6. Mechanism of Action H H N 7 R O H S N O O CO2H • C O Me H Enzyme S -CH3CO2O N O O Ser OH Ser H H N R CO2H Enzyme The acetoxy group acts as a good leaving group and aids the mechanism The Cephalosporins Generation Parenteral Agents Oral Agents First-generation Cefazolin Cefadroxil, cephalexin Second-generation Cefotetan, cefoxitin, cefuroxime Cefaclor, cefprozil, cefuroxime axetil, loracarbef Third-generation Cefotaxime, ceftazidime, ceftizoxime, ceftriaxone Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, cefixime Fourth-generation Cefepime 8. First Generation Cephalosporins Cephalothin H H N 7 S O H S 3 N OAc O CO2H • • • • • • • • • First generation cephalosporin More active than penicillin G vs. some Gram - bacteria Less likely to cause allergic reactions Useful vs. penicillinase producing strains of S. aureus Not active vs. Pseudonomas aeruginosa Poorly absorbed from GIT Administered by injection Metabolised to give a free 3-hydroxymethyl group (deacetylation) Metabolite is less active 8. First Generation Cephalosporins Cephalothin - drug metabolism H H N 7 S O H H H N S 3 N O CO2H OAc S Metabolism O H S N OH O CO2H Less active OH is a poorer leaving group Strategy • Replace the acetoxy group with a metabolically stable leaving group 8. First Generation Cephalosporins Cephaloridine H H N 7 S O H S 3 N N O CO2 • The pyridine ring is stable to metabolism • The pyridine ring is a good leaving group (neutralisation of charge) • Exists as a zwitterion and is soluble in water • Poorly absorbed through the gut wall • Administered by injection 8. First Generation Cephalosporins Cefalexin H2N H H H N 7 O H S 3 N Me O CO2H • The methyl group at position 3 is not a good leaving group • The methyl group is bad for activity but aids oral absorption mechanism unknown • Cefalexin can be administered orally • A hydrophilic amino group at the a-carbon of the side chain helps to compensate for the loss of activity due to the methyl group First Generation Cephalosporins Cefazolin Cefadroxil Cefalexin First Generation Cephalosporins include Cefazolin (parenteral) as well as cefadroxil and cefalexin (oral). Gram-positive bacteria Streptococcus pyogenes, Some virdans streptococci, Some Staphylococcus aureus, Some Streptococcus pneumoniae Gram-negative bacteria Some Eschericia coli, Some Klebsiella pneumoniae, Some Proteus mirabilis 9. Second Generation Cephalosporins 9.1 Cephamycins H OMe H N HO2C H2N H O S N O O CO2H C NH2 Cephamycin C O • Isolated from a culture of Streptomyces clavuligerus • First b-lactam to be isolated from a bacterial source • Modifications carried out on the 7-acylamino side chain 9. Second Generation Cephalosporins 9.1 Cephamycins H OMe H N 7 S O S 3 N O CO2H • • • • • O C NH2 Cefoxitin O Broader spectrum of activity than most first generation cephalosporins Greater resistance to b-lactamase enzymes The 7-methoxy group may act as a steric shield The urethane group is stable to metabolism compared to the ester Introducing a methoxy group to the equivalent position of penicillins (position 6) eliminates activity. 9. Second Generation Cephalosporins 9.2 Oximinocephalosporins Me O N C O H H N O H N O O CO2H • • • • • • Cefuroxime S C NH2 O Much greater stability against some b-lactamases Resistant to esterases due to the urethane group Wide spectrum of activity Useful against organisms that have gained resistance to penicillin Not active against P. aeruginosa Used clinically against respiratory infections • Second generation • The second-generation cephalosporins have a greater Gram-negative spectrum while retaining some activity against Gram-positive cocci. They are also more resistant to beta-lactamase. • • • • Cefaclor (Ceclor, Distaclor, Keflor, Raniclor) Cefonicid (Monocid) Cefprozil (cefproxil; Cefzil) Cefuroxime (Zinnat, Zinacef, Ceftin, Biofuroksym) • Cefuzonam Forms of Cefuroxime (2nd generation cephalosporin) Cefuroxime sodium (ZINACEF) Cefuroxime axetil (CEFTIN) More second generation cephalosporins: Loracarbef (Lorabid) The Second-generation cephalosporins include Cefotetan, cefoxitin, and cefuroxime (all parenteral) as well as Cefaclor, cefprozil, cefuroxime axetil, and loracarbef (all oral). Gram-positive bacteria True cephalosporins have activity equivalent to first-generation agents. Cefoxitin and cefotetan have little activity Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis, Haemophilus influenzae, Neisseria spp. Anaerobic bacteria Cefoxitin and cefotetan have moderate anaerobic activity. 10. Third Generation Cephalosporins Oximinocephalosporins R Me Aminothiazole ring O N H2N S N C H H N H S CH2S N N O Cefotaxime Ceftizoxime CH2OCOMe H Me N R O N Ceftriaxone OH O CO2H • • • • • • • Aminothiazole ring enhances penetration of cephalosporins across the outer membrane of Gram - bacteria May also increase affinity for the transpeptidase enzyme Good activity against Gram - bacteria Variable activity against Gram + cocci Variable activity vs. P. aeruginosa Lack activity vs MRSA Generally reserved for troublesome infections Ceftriazone (Rocephin) is a popular third generation cephalosporin It is the drug of choice for bacterial meningitis 10. Third Generation Cephalosporins Oximinocephalosporins Me Me O N C S N H 2N CO2H H H N O H S N N O CO2 Ceftazidime • • • • Injectable cephalosporin Excellent activity vs. P. aeruginosa and other Gram - bacteria Can cross the blood brain barrier Used to treat meningitis The Third-generation Cephalosporins include Cefotaxime, ceftazidime, ceftizoxime, and ceftriaxone (all parenteral) as well as Cefdinir, cefditoren, cefpodoxime proxetil, ceftibuten, and cefixime (all oral). Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptococcus pneumoniae, Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Some Enterobacteriaceae. Anaerobic bacteria Atypical bacteria Spirochetes Borrelia burgorferi 11. Fourth Generation Cephalosporins Oximinocephalosporins Me O N H2N S R N C H H N O H Me S N N R O CO2H • • • • • • CH2 CH2 N Cefipime Cefpirome Zwitterionic compounds Enhanced ability to cross the outer membrane of Gram negative bacteria Good affinity for the transpeptidase enzyme Low affinity for some b-lactamases Active vs. Gram + cocci and a broad array of Gram - bacteria Active vs. P. aeruginosa Fourth Generation Cephalosporins include cefepime (parenteral). Gram-positive bacteria Streptococcus pyogenes, Viridans streptococci, Many Streptocossus pneumoniae. Modest activity against Staphylococcus aureus Gram-negative bacteria Escherichia coli, Klebsiella pneumoniae, Proteus spp. Haemophilus influenzae, Neisseria spp. Many other Enterobacteriaceae, Pseudomonas aeruginosa. Anaerobic bacteria Atypical bacteria Newer b-Lactam Antibiotics Thienamycin (Merck 1976)(from Streptomyces cattleya) Acylamino side chain absent OH Plays a role in ß-lactamase resistance Opposite stereochemistry to penicillins Carbon H H H3C NH3 S N O CO2 Double bond leading to high ring strain and an increase in b-lactam ring reactivity Carbapenam nucleus • • • • • Potent and wide range of activity vs Gram + and Gram - bacteria Active vs. Pseudomonas aeruginosa Low toxicity High resistance to b-lactamases Poor stability in solution (ten times less stable than Pen G) Newer b-Lactam Antibiotics Thienamycin analogues used in the clinic H OH Me O H OH Me NH HN H N CO2 H H O O C N Me Meropenem S N Me H N Me O H OH Imipenem S CO2 H H N Me O C N H Ertapenem(2002) S N CO2 CO2 Primaxin = Imipenem + Cilastatin Cilastatin is an inhibitor of a human enzyme, renal dehydropeptidase, which degrades carbapenems Meropenem, Merrem, AstraZeneca Ertapenem, Invanz, Merck The Carbapenems include Imipenem/cilstatin, Meropenem, and Ertapenem (all parenteral) Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Modest activity against Staphylococcus aureus, Some enterococci, Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Neisseria spp., Enterobacteriaceae, Pseudomonas aeruginosa Anaerobic bacteria Bacteroides fragilis, Most other anaerobes. Newer b-Lactam Antibiotics Clinically useful monobactam Aztreonam • • • • Administered by intravenous injection Can be used for patients with allergies to penicillins and cephalosporins No activity vs. Gram + or anaerobic bacteria Active vs. Gram - aerobic bacteria The Monobactams include only Aztreonam, which is parenteral Gram-positive bacteria Gram-negative bacteria Anaerobic bacteria Atypical bacteria Haemophilus influenzae, Neisseria spp. Most Enterobacteriaceae, Many Pseudomonas aeruginosa. Vancomycin Mechanism of Action of Vancomycin Vancomycin binds to the D-alanyl-D-alanine dipeptide on the peptide side chain of newly synthesized peptidoglycan subunits, preventing them from being incorporated into the cell wall by penicillin-binding proteins (PBPs). In many vancomycin-resistant strains of enterococci, the D-alanyl-D-alanine dipeptide is replaced with D-alanyl-D-lactate, which is not recognized by vancomycin. Thus, the peptidoglycan subunit is appropriately incorporated into the cell wall. • http://student.ccbcmd.edu/courses/bio141/lecg uide/unit2/control/vanres.html • LINK Antimicrobial Activity of Vancomycin Gram-positive bacteria Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Some enterococci. Gram-negative bacteria Anaerobic bacteria Clostridium spp. Other Grampositive anaerobes. Atypical bacteria Daptomycin • • • Daptomycin is a lipopeptide antibiotic Approved for use in 2003 Lipid portion inserts into the bacterial cytoplasmic membrane where it forms an ion-conducting channel. Antimicrobial Activity of Daptomycin Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci. Gram-negative bacteria Anaerobic bacteria Atypical Some Clostridium spp. Rifamycins • Rifampin is the oldest and most widely used of the rifamycins • Rifampin is also the most potent inducer of the cytochrome P450 system • Therefore, Rifabutin is favored over rifampin in individual who are simultaneously being treated for tuberculosis and HIV infection, since it will not result in oxidation of the antiviral drugs the patient is taking • Rifaximin is a poorly absorbed rifamycin that is used for treatment of travelers’ diarrhea. The Rifamycins include Rifampin, Rifabutin, Rifapentine, and Rifaximin, all of which can be administered orally. Rifampin can also be administered parenterally. Gram-positive bacteria Staphylococci Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis Anaerobic bacteria Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex, Mycobacteriumleprae. Aminoglycosides The structure of the aminoglycoside amikacin. Features of aminoglycosides include amino sugars bound by glycosidic linkages to a relatively conserved six-membered ring that itself contains amino group substituents. Bacterial resistance to aminoglycosides occurs via one of three mechanisms that prevent the normal binding of the antibiotic to its ribosomal target: (1) Efflux pumps prevent accumulation of the aminoglycoside in the cytosol of the bacterium. (2) Modification of the aminoglycoside prevents binding to the ribosome. (3) Mutations within the ribosome prevent aminoglycoside binding. The Aminoglycosides include Streptomycin, Gentamicin, Tobramycin, and Amikacin (all parenteral), as well as Neomycin (oral). Gram-positive bacteria Used synergistically against some: Staphylococci, Streptococci, Enterococci, and Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Enterobacteiaceae, Pseudomonas aeruginosa Anaerobic bacteria Atypical bacteria Mycobacteria Mycobacterium tuberculosis, Mycobacterium avium complex. Macrolides and Ketolides The structures of erythromycin and telithromycin Circled substituents and distinguish telithromycin from the macrolides. Substituent allows telithromycin to bind to a second site on the bacterial ribosome. The macrolide group consists of Erythromycin, Clarithromycin, and Azithromycin (all oral, with erythromycin and azithromycin also being available parenterally). Gram-positive bacteria Some Streptococcus pyogenes. Some viridans streptococci, Some Streptococcus pneumoniae. Some Staphylococcus aureus. Gram-negative bacteria Neiseria spp. Some Haemophilus influenzae. Bordetella pertussis Anaerobic bacteria Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila, Some Rickettsia spp. Mycobacteria Mycobacterium avium complex, Mycobacterium leprae. Spirochetes Treponema pallidum, Borrelia burgdorferi. The related ketolide class consists of Telithromycin (oral). Gram-positive bacteria Streptococcus pyogenes, Streptococcus pneumoniae, Some Staphylococcus aureus Gram-negative bacteria Some Haemophilus influenzae, Bordetella pertussis Anaerobic bacteria Atypical bacteria Chlamydia spp. Mycoplasma spp. Legionella pneumophila The Tetracycline Antibiotics The structure of tetracycline The Tetracycline Class of Antibiotics consists of Doxycycline and Tigecycline (parenteral) as well as Tetracycline, Doxycycline and Minocycline (oral) Gram-positive bacteria Some Streptococcus pneumoniae Gram-negative bacteria Haemophilus influenzae, Neisseria meningitidis Anaerobic bacteria Some Clostridia spp. Borrelia burgdorferi, Treponema pallidum Atypical bacteria Rickettsia spp. Chlamydia spp. Tigecycline The antimicrobial activity of Tigecycline (parenteral) Gram-positive bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci, Listeria monocytogenes Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Enterobacteriaceae Anaerobic bacteria Bacteroides fragilis, Many other anaerobes Atypical bacteria Mycoplasma spp. Chloramphenicol The Antimicrobial Activity of Chloramphenicol Gram-positive bacteria Streptococcus pyogenes, Viridans group streptococci. Some Streptococcus pneumoniae Gram-negative bacteria Haemophilus influenzae, Neisseria spp. Salmonella spp. Shigella spp. Anaerobic bacteria Bacteroides fragilis. Some Clostridia spp. Other anaerobic Gram-positive and Gram negative bacteria Atypical bacteria Rickettsia spp. Chlamydia trachomatis, Mycoplasma spp. Clindamycin The Antimicrobial Activity of Clindamycin (both oral and parenteral) Gram-positive bacteria Some Streptococcus pyogenes, Some viridans group streptococci. Some Streptococcus pneumoniae, Some Staphylococcus aureus Gram-negative bacteria Anaerobic bacteria Atypical bacteria Some Bacteroides fragilis, Some Clostridium spp. Most other anaerobes. Streptogramins The Antimicrobial Activity of Quinupristin/Dalfopristin (parenteral) Gram-positive bacteria Gram-negative bacteria Anaerobic bacteria Atypical bacteria Streptococcus pyogenes, Viridans group streptococci, Streptococcus pneumoniae, Staphylococcus aureus, Some enterococci. The Oxazolidinones The structure of Linezolide The Antimicrobial Activity of Linezolid (both oral and parenteral) Gram-positive bacteria Gram-negative bacteria Anaerobic bacteria Atypical bacteria Streptococcus pyogenes. Viridans group streptococci, Streptococcus pneumoniae, Staphylococci, Enterococci.