University:
West Coast University
Course:
PHAR 837 | IPC Infectious Diseases I
Academic year:

2024
Views:

71

Pages:

77
Author:

Asal A.

Antimicrobial Agents: Inhibitors of Cell Wall Synthesis Adam Kassan, PhD Associate Professor, Pharmaceutical Sciences West Coast University, School of Pharmacy akassan@westcoastuniversity.edu 323-454-5071 ext 47071 Bacteriawiocanyon Bacterial Cell Wall • • willdie Rigidity and shape Protection from osmotic pressure I • • • Thick peptidoglycan  20-80 layers Teichoic and lipoteichoic acids Various proteins • amino • acids peptide • Thin peptidoglycan  8-11 layers Outer membrane  porins  lipopolysaccharides Various proteins peptide 1 1006 glucosesugar Peptidoglycan (Murein) Structure 78Peptidoglycan monomer (building block): sugar(derivative of glucose): • 2 joined amino saccharides  N-acetylglucosamine (NAG)  N-acetylmuramic acid (NAM)Mosominoacidoreattached o pentapeptide, where the 3rd amino ac. suggers - lysine (Lys) in gram +ve - diaminopimelic ac (DAP) in gram -ve pewter 50m28s Be Peptidoglycan of S. aureus Peptidoglycan of E. coli Peptidoglycan (Murein) Structure those Peptidoglycan polymer: Alternating NAG-NAM • Linked in rows by transglycosylase tNAG NAMconnetedbythis  to form carbohydrate backbone enzyme • Adjacent rows are linked by polypeptides or Aminoacid  by transpeptidase (penicillin binding protein PBP) penjpeptiden  direct cross-link in gram -ve  pentapeptide interbridge in gram +ve o consisting of 5 glycines NAM YAntapeptide entapertoconnepheenzymeistranspeptidase Peptidoglycan Biosynthesis 3 stages: I • Cytoplasmic  synthesis of precursors (NAG, NAM) see • 2 Cell Membrane  transport from cytosol to peptidoglycan haveit • 3 Cell wall no Humansdon't  crosslinking of peptidoglycans β-Lactams • Largest group of antibiotics Inhibitors of cell wall synthesis β-Lactams Penicillins Cephalosporins Glycopeptides Carbapenems D-Cycloserine Monobactams Bacitracin Fosfomycin β-Lactams • Share a common structural feature:  β-lactam ring o essential four-member ring pacemffitt pinhibittranspeptidase β-Lactams: Mechanism of Action Inhibition of cross-linking of peptidoglycan • Weakening of cell wall • Osmotic pressure  cell will swell and burst • Bactericidal β-Lactams: Mechanism of Action peptidase trans A topeptide β-lactam antibiotic binds the PBP pen • Mimics the conformation taken by at D-Ala-D-Ala during the cross-linking reaction • PBPs attempt to catalyze the β-lactam ring  blocking the peptide side chain cross-linking o resulting in inactivation of the PBPs PBP Goo PBP penicillin transpeptide protein Binding β-Lactams: Penicillins Introduction • One of the largest and oldest classes of antimicrobial agents (Fleming 1928) • Natural penicillins (G and V)  extracted from cultures of the mold Penicillium notatum • Semisynthetic penicillins  methicillin, oxacillin, ampicillin, amoxicillin… • Both the natural and semisynthetic penicillins are bactericidal memberng E β-Lactams: Penicillins SAR IO • Amino acyl side chain involved in binding • Stereochemistry of the bicyclic ring with Amide essential Cis Stereochemistry essential respect to the acylamino side chain O Sulphur H H H N C S • β-lactam ring is essential Me R • Carboxylic acid involved in binding N Me • Bicyclic system (β-lactam and thiazolidine O Carboxylic acid essential -Lactam essential ring) is important (increases β-lactam CO2H ring strain) Bicyclic system essential • Sulphur is usual but not essential so Gandy β-Lactams: Natural Penicillins, Acid Sensitivity to penicilling Acyl side chain Neighbouring group participation in the hydrolysis mechanism R H C N H O N O + S N R S N R S -H+ O N O + O HN O H+ Relieves ring strain hasto bed penicillin I no β-Lactams: Natural Penicillins, Acid Resistance oddity projectagainst a group to the acyl side group Add an electron withdrawing • To make it electron-withdrawing • To decrease the nucleophilicity of the carbonyl oxygen • To reduce the participation from the neighboring acyl group X PhO H N CH2 H C 0 electronegative oxygen O HC S R N O Penicillin V (orally active)  H N H S C O N O X= NH2, Cl, PhOCONH, heterocycles. CO2H β-Lactams: Natural Penicillins Pharmacokinetics • Poor but rapid absorption after oral administration (Pen V)  absorption impaired by food o 1-2 h before/after a meal • Distributed throughout the body  concentration in various tissues differ widely  does not readily enter CSF (penetrates easily when meningitis) • Penicillins have very short t1/2 < 1h  dosed multiple times/day (every 4-6 h) • Highly protein bound • Rapidly excreted by the kidneys (~ 90%)  increased t1/2 in renal impairment and infants • Some hepatic elimination SedinBaseandmetallo β-Lactams: Penicillins Mo thepygdomring Destroy Sensitivity to β-Lactamases • Enzymes that inactivate penicillins by opening β-lactam rings  1000 penicillin molecules are hydrolysed per second • Transferable between bacterial strains  80% Staph. infections in hospitals were resistant to penicillin by 1960 • 2 types of β-lactamases (4 clases):  serine based (class A, C, and D)  metallo-β-lactamase (class B) o NDM-1 O C H N O H S R N Me Me O NMD-1: New Delhi Metallo β-Lactamase-1 C CO2H H N H S R β-Lactamase HO2C HN Me Me CO2H against β-Lactams: Penicillins Sensitivity to β-Lactamases Use a steric shields • Block access of penicillin to the active site of the β-lactamases • Size of shield is crucial  to inhibit reaction of penicillins with β-lactamases  but not with the target transpeptidase enzyme O Bulky group C H N H H S R N Lactamase Me Me O CO2H methiwain oxacillin Nafalli g β-Lactams: Penicillins β-Lactamases-Resistant • Lack electron withdrawing groups  sensitive to acidity o not orally administered Acid Sensitivity Anscombeadminister orally eBulkygrapf t BulkygroupagainstB lactamase Coprotectect β-Lactams: Penicillins β-Lactamases-Resistant R' O C R N O H N H S N Me Bulky and electron withdrawing Isoxazole group H Me Me O CO2H Oxacillin R = R' = H Flucloxacillin R = Cl, R' = F Dicloxacillin R = Cl, R’ = Cl Cloxacillin R = Cl, R' = H (not available in the US) • Orally active  Isoxazolyl penicillin β-Lactams: Penicillins β-Lactamases-Resistant: Pharmacokinetics Isoxazolyl penicillin • Incomplete but rapid absorption after oral administration (30-50%)  absorption impaired by food o 1-2 h before/after a meal  max concentrations in the blood by 1h • Highly protein bound • t1/2 for all isoxazolyl penicillins ~30-60min • Rapidly excreted by the kidneys  no dose adjustment are needed with renal failure • Significant hepatic metabolism  excreted in the bile in Phydrophilic gram we I β-Lactams: Penicillins as Extended-Spectrum Increased hydrophilic character • Did not change the effect on gram +ve activity • Increases gram -ve activity 0 haveoutermembrane They  allow drug penetration through the porins of gram -ve outer membrane • 3 classes  Aminopenicillins 2 Carboxypenicillins 3 Ureidopenicillins β-Lactams: Penicillins Extended-Spectrum • • • • Aminopenicillins NH2 at the α-position comfort Acid resistant  presence of EWG amine group Sensitive to β-lactamase  no steric shieldas son'tbeusedagainstB factorage Well absorbed  both the amino and the carboxylic group are ionized α α β-Lactams: Penicillins Extended-Spectrum Prodrugs of Ampicillin • Increased cell membrane permeability • Polar carboxylic acid group is masked by the ester • Ester is metabolised in the body by esterases to give the active drug O H NH2 R= CH2O C CMe3 PIVAMPICILLIN C C H N H O H S O Me TALAMPICILLIN O R= Me N O O CO2R R= CH Me O C O CH2Me BACAMPICILLIN β-Lactams: Penicillins Extended-Spectrum Aminopenicillins: Pharmacokinetics • Well and rapid absorption after oral administration  absorption impaired by food (not for amoxicillin) o 1-2 h before/after a meal  max concentrations in the blood by 1-2h • Protein bound (~20%) • Rapidly excreted by the kidneys  dose adjustment are needed with renal failure • Ampicillin is also excreted in the feces β-Lactams: Penicillins Extended-Spectrum • • • • • Carboxypenicillins (anti-psuedomonal penicillins) CO2H at the α-position Active over a wider range of gram -ve bacteria than ampicillin Acid sensitive and must be injected Resistant to most β-lactamases Ticarcillin and carbenicillin are discontinued in the US CO2R CH C H N CO2H H H S O Me S O N O O Carbenicillin H Me N R=H H H N CO2H Ticarcillin S Me Me CO2H β-Lactams: Penicillins Extended-Spectrum • • • • • Ureidopenicillins (anti-psuedomonal penicillins) Urea group at the α-position It Newest class of extended-spectrum penicillins  broadest spectrum of the penicillins Administered by injection Piperacillin can be administered alongside tazobactam (Zosyn) Azlocillin and Mezlocillin are discontinued in the US O HN Azlocillin Mezlocillin MeO2S O N O N R2N NH N H H N O Piperacillin Et N N O O H N O S Me Me CO2H β-Lactams: Penicillins β-Lactamase Inhibitors Clavulanic acidtxtargatisptogtomase Sulphur replaced • Isolated from Streptomyces clavuligerus by oxygen No acylamino • Suicide substrate for β-lactamase enzymes side chain H 9 OH O • β-lactam ring 4 5 6 3  not fused to a sulfur-containing ring 7 1 2 N H  fused to an oxazolidine ring O H CO H • Structure doesn’t have an acyl-amino side chain Lactam Oxazolidine ring • Powerful irreversible inhibitor of β-lactamases (class A) beserinBase • Augmentin = amoxicillin + clavulanic acid  allows less amoxicillin per dose and an increased activity spectrum 2 β-Lactams: Penicillins β-Lactamase Inhibitors 1 2 NH 2 O NH2 NH CH2OH N O O H Clavulanic acid: Mechanism of action • Fits the active site of β-lactamase • β-lactam ring is open by serine • Intermediate reacts with NH2 • Irreversible binding 3 CO2H O O CH2OH HN H HN O Base H O OH CO2H O 4 O 5 CH2OH H2N NH NH CO2H H CH HC O O O CO2H O Irreversibly blocked CH2OH β-Lactams: Penicillins β-Lactamase Inhibitors Penicillanic acid sulphone derivatives O O O O O S Me S N Me N O CO2 Na Sulbactam Sulbactam • Broader spectrum than clavulanic ac.  class A, weak C and very weak D • Less potent • Unasyn (IV)= ampicillin + sulbactam Me N N N CO2 Tazobactam Tazobactam • Broader spectrum than clavulanic ac.  same as sulbactam • Similar potency as clavulanic acid • Zosyn (IV)= piperacillin + tazobactam AtAuboctamandRelebactom reversible andNfBigg β-Lactams: Penicillins β-Lactamase Inhibitors O Diazabicyclooctanes O NH H2N N Avibactam O SO3Na Avibactam (2015) • 1st new β-lactamase inhibitor to reach the market in over 20 years  class A, C and D HN O N O N N O SO3Na Relebactam Relebactam • An analogue approved by FDA (2019)  class A and C • Recarbrio (IV) = imipenem + cilastatin + relebactam • Unlike previous β-lactamase inhibitors  no β-lactam ring  slow, reversible inhibitors stop β-Lactams: Penicillins β-Lactamase Inhibitors Diazabicyclooctanes Mechanism of action • Cyclic urea reacts with serine residue  opened urea ring • Reversible  cyclic urea can reform  drug released from the active site • Drug is free to re-enter the active site and react once more  resulting in prolonged inhibition O H2N O N O N O O S O H2N N O O H+ OH Ser -Lactamase enzyme HN O O O S Ser -Lactamase enzyme O O β-Lactams: Penicillins Adverse Reactions • Toxic reactions  GI irritation  irritation caused by injection of penicillin o sterile abscesses if given im o thrombophlebitis if given iv • Allergic or hypersensitivity reactions  penicillins are the most common cause of drug allergies o ~10% US population is allergic  rash to anaphylaxis (very rare ~0.05% of recipients) Gosevere reaction allergic β-Lactams: Penicillins • • • • β-lactam hypersensitivity Not immunogenic by themselves  small molecule React with NH2 groups on human proteins  to create hapten carrier complex o immunogenic Dose dependent Anaphylaxis β-Lactams: Penicillins β-lactam Resistance 4 general mechanisms •d Inactivation of antibiotic by β-lactamase  most common havesomemutation Trans p eptidases •2 Modification of target PBPs  PBPs that have low affinity for binding β-lactam antibiotics  methicillin resistance in staphylococci • 3 Impaired penetration of drug to target PBPs  only in gram -ve • a Antibiotic efflux β-Lactams: Cephalosporins Introduction • Second major group of β-lactam antibiotics • Discovered from a fungal colony  Cephalosporium acremonium in Sardinian sewer water (1948) • Cephalosporin C identified in 1961 • Used in case of penicillin resistance, or allergy to penicillin • Have broader activity against gram -ve bacteria  penetrate the porins  more resistant to β-lactamases • Cephalosporins are excreted primarily by the kidney  in general, dosage adjustment with renal insufficiency semester β-Lactams: Cephalosporins SAR Osb member 5 Bicyclic system 7-Aminoadipic side chain H H N H2N H CO2H O H 7 6 8 5 N S 1 4 2 3 O O CO2H -Lactam • Similar to penicillins ring  β-lactam ring (crucial) Cephalosporin C • Different than penicillins  fused to dihydrothiazine ring instead of thiazolidine ring • Carboxylic acid at position 4 is important to binding • Bicyclic system is important in increasing ring strain • Stereochemistry is important • Acyl amino side chain at position 7 is important C Me O Dihydrothiazine ring β-Lactams: Cephalosporins Mechanism of Action we inhibittranspeptidase H H N R H S O N O O CO2H C O Me H Enzyme S -CH3CO2- O N O O Ser OH Ser H H N R 7 Enzyme CO2H β-Lactams: Cephalosporins First Generation H 2N H H N H H orally S 7 O 3 N see Me O C O 2H Cephalexin (Keflex) Cefazolin (Ancef) • Methyl group at position 3 • Lack methyl group  aids oral absorption  not absorbed from the GI tract  bad for activity (poor leaving group)  must be administered parentally (IV, IM) • A hydrophilic amino group at position 7 • Not metabolized helps to compensate for the loss of activity  excreted unchanged in urine • Can be administered orally o dose adjustment in renal failure • Not metabolized  excreted in urine o dose adjustment in renal failure β-Lactams: Cephalosporins First Generation • Generally lower activity than comparable penicillins • Better range of activity than comparable penicillins • Resistance has appeared amongst gram -ve bacteria  presence of more effective β-lactamases β-Lactams: Cephalosporins Second Generation r Cephamycins H N HO2C H NH2 OMe H H OMe H N S S 7 N O 3 NH2 O O O N 3 O CO2H Cephamycin C S O Cefoxitin (Mefoxin) CO2H O C NH2 O • Isolated from Streptomyces clavuligerus • Broader spectrum of activity than most 1st • Contains a 7-methoxy group generation cephalosporins  Steric shield • Greater resistance to β-lactamase enzymes protectagainBlactose • Good metabolic stability to esterases  7-methoxy group acts as a steric shield  urethane group (position 3) • t1/2 ~ 41-59 min • Excreted unchanged in urine β-Lactams: Cephalosporins Second Generation Cephamycins Cefotetan (Cefotan) • Resistance to β-lactamase enzymes  7-methoxy group acts as a steric shield • N-methylthiotetrazole ring (NMTT)  hypoprothrombinemia o oral VitK dehydrogenase  disulfiram reactions or Actonaldehyde o use of alcohol must be avoided β-Lactams: Cephalosporins Second Generation 2 Me Oximinocephalosporins O N C O H H N O H S N Actasstoried Cefuroxime (Zinacef, Ceftin) O O pm CO2H C NH NH2 O • Iminomethoxy group 818  significantly increase the stability against β-lactamases • Urethane group  resistant to esterases • Wide spectrum of activity  most commonly used oral cephalosporin in the USA • t1/2 ~1-2h • Excreted unchanged in urine β-Lactams: Cephalosporins Third Generation Oximinocephalosporins O N H2N S Me R Me N C H H N O H Cefotaxime Ceftizoxime CH2OCOMe H CH2S 3 O CO2H O CO2H N Me S N Me R N N N Ceftriaxone OH O C S N H2N H H N O H S N N O Ceftazidime (Fortaz) CO2 • Replacement of furan ring with an aminothiazole ring • Pyridine  ↑ penetra on across gram -ve outer membrane  zwitterion  ↑ aﬃnity for the transpeptidase the  stable metabolism morepowerful • Substitution at 3 leads to different drugs drugs  rapid bacterial penetration • Ceftriaxone (Rocephin): t1/2 ~8h • Cross blood brain barrier  allows 1 daily dose  treat meningitis • Excreted unchanged in urine (67%) • Injectable  the rest in feces as inactive drug • Excreted unchanged in urine β-Lactams: Cephalosporins Fourth Generation Oximinocephalosporins Me O initstronger N H2N get • Aminothiazole ring S R N C H H N O H Me CH 2 N S N R O CO2 CH 2 N O Cefepime (Maxipime) Cefpirome (not available in the US) should • Iminomethoxy group steric PstabilityagainstB lactones • Zwitterionic compounds  rapid bacterial penetration  good affinity for the transpeptidase enzyme • Penetrates CSF • t1/2 ~ 2 h • Excreted in urine Targetistrenspeptidase g β-Lactams: Cephalosporins Fifth Generation conbindtotet trenspetidase spotenspeptidaseismatted • Anti-MRSA cephalosporins • Bind:  normal PBPs  abnormal PBPs o PBP-2a (MRSA) o PBP-2x (MDRSP) • Zwitterionic compounds  better penetration in gram -ve β-Lactams: Cephalosporins Fifth Generation Ceftolozane (2015) • Basic amino group at position 3 of pyrazole ring  ↑ permeability against P. aeruginosa Ceftaroline (Teflaro) (2010) • Basic side chain at position 4 • Prodrug (ceftaroline fosamil)  ↑ ac vity against strains of P. aeruginosa that • 1,3-thiazole ring produce class C β-lactamases  important for the • Urea group Ed side effects activity against MRSA  significantly ↓ convulsive • Rapid renal elimination • Available in combination with tazobactam  t1/2~2h (Zerbaxa) β-Lactams: Cephalosporins Adverse Reactions a • Hypersensitivity reactions are the most common side effects  similar to those caused by the penicillins 2 • GI effects  common adverse reaction  diarrhea, nausea, vomiting, abdominal pain, anorexia, dyspepsia 3 • Local reaction  localized pain, induration, and swelling when given IM  thrombophlebitis when given IV 9• Nephrotoxicity s• Superinfection β-Lactams: Cephalosporins Adverse Reactions: Cross-Reactivity With Penicillins • Allergy  less common and less severe than with penicillin o cross-hypersensitivity with penicillin is ~ 2%  mild-delayed penicillin allergy → cau ously administer  severe penicillin allergy → avoid Ampicillin Cephalexin Amoxicillin Aminocephalosporins that have shared chemical side chains Cefaclor w yo β-Lactams: Carbapenems Iris T Opposite stereochemistry to penicillins Acylamino side chain absent OH Plays a role in -lactamase resistance • Carbapenem nucleus  S replaced by C • Absence of acyl amino side chain • Hydroxyethyl side chain  high resistance to β-lactamase • Opposite stereochemistry to penicillin  high resistance to β-lactamase • Double bond  increase ring strain and reactivity Carbon NH3 H H H3C S N O CO2 Carbapenam nucleus Thienamycin (Merck 1976) Double bond leading to high ring strain and an increase in -lactam ring reactivity β-Lactams: Carbapenems Thienamycin • • • • • • Imipenem (Primaxin) 1st carbapenem • Semi synthetic  isolated from Streptomyces cattleya (1976)  replacement of amino group to a gresty Potent and wide range of activity vs gram +ve and-ve less nucleophilic group Low toxicity • Not absorbed from the GI (IV) Highly resistant to β-lactamases • Rapid hydrolysis by dehydropeptidase Poor metabolic and chemical stability on the brush border of renal tubules  nucleophilic amino group  nephrotoxic metabolites Not absorbed from the GI  combine with cilastatin  dose adjustment  t1/2 ~1h β-Lactams: Carbapenems • Clinically important “last resort” antibiotics  broadest spectrum of all β-lactam antibiotics  effective against β-lactam resistant bacteria • Emergence of superbugs  Carbapenem-Resistant Enterobacteriaceae (CRE) o New Delhi metallo-beta-lactamase-1 (NDM-1) o no new antibiotics in development for CRE • Most common adverse effects (more common with imipenem)  nausea, vomiting, diarrhea, rashes, and reactions at the infusion sites • Excessive levels of imipenem in renal failure may lead to seizures • Cross-reactivity with penicillins is less than 1% we onlygram β-Lactams: Monobactams Me Me OH CO2H N H N O O H • • • • CO2H H N N CO2H H N N O ceftazidime H H2N O OH ongren only an A Nocardicin Isolated from natural sources Monocyclic β-lactam ring Moderately active in vitro vs narrow group of gram –ve; inactive vs. gram +ve  binds to a different type of PBP Low toxicity H2N S N O O • • • • • • • • Me SO3 Aztreonam (Azactam) Administered by injection (IV, IM) Can be used for patients with allergies to penicillins and cephalosporins Inactive vs. gram +ve or anaerobic Resistant to Ser and metallo-β lactamases Similar side chain to Ceftazidime Penetrate BBB t1/2 ~ 1–2 hours Excreted unchanged in urine only yo Glycopeptides: Introduction destine emplsm papton once • Vancomycin (1956) and vancomycin analogues • From the verb “to vanquish” • Narrow spectrum imma  not active against gram -ve • Bactericidal • Produced by Streptomyces orientalis • Last resort in treating drug resistant infections inside  such as MRSA mo p lactamcontgo • Blocks transglycosidation But D aloni D alonian Glycopeptides Vancomycin SAR • Derived biosynthetically from a linear heptapeptide • Contains 5 aromatic groups  important for: É and fixed o heptapeptide rigidity conformation - essential for the activity • 2 sugars Peptide chain Vancomycin (Vancocin) Glycopeptides Vancomycin Mechanism of Action Vancomycin ...................... ........ Growing cell wall Chen lab. University of South Florida Crosslinking P yo Bindweed NEG Cell membrane .. Transglycosidation . Gly Carrier lipid Cytoplasm L-Ala D-Glu L-Lys NAM L-Ala • Blocks transglycosidation  prevents further elongation of peptidoglycan Amino acid EE D-Ala D-Ala-D-Ala NAG thetaille Bindto peptidase oftransGlycopeptides t Vancomycin Mechanism of Action Vancomycin Building block Cell membrane • • • • Provides binding pocket for the biosynthetic building block Binds to the tail of the building block’s peptide chain Caps the building block Disguises the building block from the transglycosidation enzyme Glycopeptides Vancomycin Mechanism of Action H-bonding interactions between the peptide and the biosynthetic building block Cell wall building block L-Lys-D-Ala-D-Ala ‘tail’ Glycopeptides Vancomycin Mechanism of Action Growing cell wall .. .. . .. .. . Vancomycin dimer . Building block I • Dimerisation occurs protegerstandong  dimer is highly stable • Large vancomycin molecule acts as a steric shield  blocking access to the transglycosidase and transpeptidase enzymes Glycopeptides Vancomycin Mechanism of Action H O Me O H N N O H Me H Cell wall building block D-Ala-D-Ala-L-Lys- tail Tail 2 O Heptapeptide backbone or Binding interactions in dimer i Heptapeptide backbone O Cell Cellwall wallbuilding buildingblock block H N H Me H O N O Me O L-Lys-D-Ala-D-Ala tail H Tain Glycopeptides Vancomycin Pharmacokinetics • Administered IV for systemic effect • Poorly absorbed from the intestinal tract  administered orally only for the treatment of colitis caused by C. difficile • Widely distributed  CSF levels of 7-30% of blood levels if there is meningeal inflammation  t1/2~6h  ~30% bound to plasma proteins • Excreted by glomerular filtration (~90%)  accumulation in renal insufficiency o monitor in renal impairment Glycopeptides Vancomycin Adverse Effects Most reactions are relatively minor and reversible Infusion-related: • With high doses  can cause nephrotoxicity and ototoxicity • With rapid infusion rates  can cause anaphylactoid reaction o hypotension, wheezing, dyspnea, urticaria, pruritis, and red man syndrome (rash)  infuse slowly and premedication with histamine blockers Glycopeptides alaninereplaced MoD by Vancomycin Resistance Dante • Slow to develop  Vancomycin-resistant enterococci (VRE) (1989)  Vancomycin-resistant Staphylococcus aureus (VRSA) (1996) • Due to mutation in pentapeptide chain of cell wall building block • terminal D-alanine replaced by D-lactate • resulting in ester link instead of amine link • removal of NH group involved in hydrogen bonding • sufficient to weaken the binding affinity and make the antibiotic ineffective Mutation Cell wall building block Cell wall building block L-Lys-D-Ala-D-Ala tail omingnoup Hsbond L-Lys-D-Ala-D-Lactate tail oxygen Glycopeptides Vancomycin Analogues • Eremomycin  naturally occurring glycopeptide • Telavancin (Vibativ) (2009)  analogue of eremomycin  t1/2~8h  Teratogenic (avoid in pregnant women)  penetrates epithelium and skin blister fluid o good for complicated skin infections • Oritavancin (Orbactiv) (2014)  analogue of eremomycin  1000X more active than vancomycin  t1/2 ~10 days o allow for intermittent dosing (~weekly) Glycopeptides Vancomycin Analogues Teicoplanin (Targocid) • Isolated from a soil microorganism Actinoplanes teichomyceticus • Unlike vancomycin, does not dimerize • Less toxic than vancomycin • Not available in the US Dalbavancin (Dalvance) (2014) • Analogue of teicoplanin • t1/2 ~10 days  allow for weekly dosing or less • ~50% unchanged in urine • Dose adjustment in renal failure Glycopeptides Vancomycin Analogues Glycopeptides • Very complex drug  difficult to synthesize analogues • Solution:  Simplified analogues o capable of binding D-Ala-D-Ala or D-Ala-D-Lac  lead compounds for development of future antibiotics yocellwallinhibitors Actingoncannedcoatosol Cycloserine (Seromycin®) ...................... ........ Growing cell wall Crosslinking ... . Transglycosidation NAG Gly Carrier lipid Cell membrane Cytoplasm L-Ala D-Glu L-Lys NAM L-Ala Amino acid D-Ala D-Ala-D-Ala Cycloserine O H N HO O H NH2 D-Cycloserine D-Cycloserine Me O H NH2 D-Alanine D-Alanine D-Cycloserine as a mimic to D-Ala • Natural product by Streptomyces orchidaceous • Used almost exclusively to treat tuberculosis  caused by strains of Mycobacterium tuberculosis • Acts within the cytoplasm  to block biosynthesis of D-Ala-D-Ala • Mimics the structure of:  D-Ala o therefore, inhibits L-alanine racemase - responsible for racemizing L-Ala to D-Ala  D-Ala-D-Ala ligase o responsible for linking the 2 D-Ala units together • Serious, dose-related CNS toxicity with headaches, tremors, acute psychosis, and convulsions  maintain oral dosages below 0.75g/dl 5 plod too poutpentaffsteangember nay PBacitracin or (Baciim) Nepht . .. .. .. .. .. .. . .. ... .. .. .. ... ... ... Growing cell wall -Lactams Vancomycin Crosslinking Bacitracin Cell membrane ... . Transglycosidation Gly Carrier lipid Cytoplasm L-Ala D-Glu L-Lys NAM L-Ala Amino acid D-Ala Cycloserine D-Ala-D-Ala NAG • Cyclic polypeptide produced by Bacillus subtilis (1943) • Binds to the lipid carrier  prevents transporting the NAM/pentapeptide building block across the cell membrane • Highly nephrotoxic when administered systemically and is only used topically • Poorly absorbed, and topical application results in local antibacterial activity Fosfomycin (Monurol) • Produced by Streptomyces fradiae • Broad spectrum • Only oral preparation is approved in the US  oral bioavailability is approximately 40% • Used for treatment of uncomplicated UTIs • t1/2 ~ 4 h • The active drug is excreted by the kidney • Inhibits cytoplasmic enolpyruvate transferase  early step of wall synthesis Agents Disrupting Cell Membrane Function lessacidicfosfogid humancallmenbrae a morecholesterol Cell Membrane Structure • Phospholipid bilayer with embedded proteins  fluid mosaic model • Functions in:  providing site for cell signaling, energy reactions, and synthesis  passage of nutrients into the cell and discharge of wastes  cell membrane is selectively permeable Agents Disrupting Cell Membrane Function peptides all theyre comin odds Inhibitors of cell membrane Tunneling agents • Gramicidin A Ionophores • Polymyxin B • Valinomycin (animals) Cyclic lipopeptides • Daptomycin Agents Disrupting Cell Membrane Function Gramicidin A to Allowlikage Topical wounds • • • • • • Val-Gly-Ala-Leu-Ala-Val-Val-Val-Trp-Leu-Trp-Leu-Trp-Leu-Trp-NH-CH2-CH2-OH Gramicidin A Peptide antibiotic (15 amino acid) Thought to form a helix in the cell membrane Two helices aligned end to end to form an ‘escape tunnel’ Hydrophobic exterior interacts with cell membrane lipids Hydrophilic interior allows uncontrolled passage of ions One of the three constituents of consumer antibiotic polysporin Cell Ions Agents Disrupting Cell Membrane Function Inhibitors of cell membrane Tunneling agents • Gramicidin A peptides Ionophores • Polymyxin B • Valinomycin (animals) Cyclic lipopeptides • Daptomycin Agents Disrupting Cell Membrane Function Polymyxin B DAB: α,γ-diaminobutyric acid • Polypeptide derived from a soil bacterium  Bacillus polymyxa • Binds to the phosphate group of the cell membrane  cell membrane disruption  leakage of small molecules such as nucleosides Agents Disrupting Cell Membrane Function Polymyxin B: Adverse Effects Mainly when used IV • Renal  nephrotoxicity o most common effect • Neurological  dizziness, mental status change, neuromuscular blockade Agents Disrupting Cell Membrane Function Cyclic lipopeptides Bindsto calyembroe in a Daptomycin (Cubicin) we • Derived from Streptomyces roseosporus money • Poor oral absorption  IV slow infusion >30 min  t1/2~8-9h o allow once-daily dosing • Active primarily against gram +ve • Used for skin and soft skin infections  not useful in treatment of pneumonia o drug is inactivated by pulmonary surfactant cordependt Agents Disrupting Cell Membrane Function Cyclic lipopeptides Daptomycin (Cubicin) • Binds to cell membrane  causes depolarization, loss of membrane potential, and cell death • Renal elimination (80%)  adjustment in renal failure Agents Disrupting Cell Membrane Function Cyclic lipopeptides: Adverse Effects • Myalgia  can lead to rhabdomyolysis o weekly monitor CK • Eosinophilic pneumonia

Antimicrobial Agents: Inhibitors of Cell Wall Synthesis

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