IID 03: Chemistry of Beta Lactams Flashcards
Which antibiotics affect the cell wall?
- penicillins
- monobactams
- cephalosporins
- carbapenems
- vancomycin
- televancin
- teicoplanin
- fosfomycin
Which antibiotics affect the cell membrane?
- televancin
- teicoplanin
- daptomycin
Which antibiotics affect protein synthesis?
- macrolides & ketolides
- lincosamides
- linezolid
- tetracyclines & glycylcyclines
- aminoglycosides
Which antibiotics affect folate metabolism?
- sulfonamides
- trimethoprim
Which antibiotics affect DNA conformation?
- fluoroquinolones
Which antibiotics affect macromolecule function?
- metronidazole
- nitrofurantoin
Describe gram-positive cells.
- appear smooth in a scanning electron micrograph
- composed of a single layer of peptidoglycan (B)
- ie. group B streptococci, S. aureus, S. epidermidis, S. pneumoniae, S. pyogenes, S. viridans, E. faecalis, B. cereus, B. anthracis, B. subtilis, C. difficile, P. acnes, L. monocytogenes
Describe gram-negative cells.
- have an undulating surface
- have three layers
- ie. E. coli, K. pneumoniae, S. marcescens, H. influenzae, P. aeruginosa, P. mirabilis, B. typhosus, N. gonorrhoeae, N. meningitidis, P. vulgaris, H. pylori, V. cholerae
Bacterial Cell Wall
Describe the enzymatic reaction that bacterial transpeptidases catalyze to form the peptidoglycan cell wall.
transpeptidase mechanism (D-Ala-D-Ala hydrolysis)
- Ser residue (oxygen atom) within transpeptidase active site attacks the carbonyl carbon between D-Ala-D-Ala
- tetrahedral intermediate subsequently collapses to release the C-terminal D-Ala
- N-terminus of Gly residue attacks the ester bond between D-Ala and active site Ser residue
Chemistry of Penicillins
Compare and contrast the D-Ala-D-Ala (transpeptidase substrate) structure to penicillin’s structure, and show the mechanism of inhibition.
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Chemistry of Penicillins
Describe structural differences between penicillins that target Gram-positive versus Gram-negative bacteria as the chemical basis for the spectra of antibiotic activities.
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Chemistry of Penicillins
What chemical instability prevented Fleming from isolating penicillin G via acid extraction?
penicillin G acid sensitivity
Chemistry of Penicillins
What characteristics of penicillin G make it acid sensitive? (3)
- ring strain – acid-catalyzed ring opening relieves ring strain on beta-lactam ring
- pi electrons out of carbonyl plane – no resonance stabilization with amide nitrogen, therefore making beta-lactam carbonyl group highly reactive
- neighbouring group participation (NGP) – influence of acyl side chain in the hydrolysis of the beta-lactam amide bond
Chemistry of Penicillins
How does penicillin G inhibit bacterial transpeptidases? (2)
- molecular mimicry – similar backbone structures between the natural transpeptidase substrate D-Ala-D-Ala and the 6-amino penicillinic acid (6-APA) scaffold
- acts as an irreversible inhibitor of the bacterial transpeptidase enzyme – inactivates the enzyme by covalently attaching to the active site Ser residue and preventing the subsequent conjugation between D-Ala and Gly residues
Chemistry of Penicillins
What is penicillin’s mechanism of action?
- transpeptidase Ser residue attacks the lactam carbonyl carbon, therefore forming a covalent attachment between transpeptidase enzyme and inhibitor
- lactam ring opens, but ester linkage remains intact to block substrate binding
Chemistry of Penicillins
How can some penicillins be taken orally?
- semi-synthetic penicillins featuring an electron-withdrawing group (EWG) attached to the C-alpha do not undergo NGP
(see notes – compare structures with penicillin G structure)
Chemistry of Penicillins
What is the bacterial resistance mechanism?
beta-lactamases hydrolyze ~1000 penicillin molecules per second
- virtually all gram-negative bacteria produce beta-lactamases
- bacterial S. aureus (gram-positive) is vulnerable to acid-resistant penicillins, but can develop drug resistance
Chemistry of Penicillins
What are methicillin-resistant S. aureus (MRSA) bacteria?
95% of S. aureus strains detected in hospitals have become resistant to penicillins like methicillin
Chemistry of Penicillins
Describe oral penicillins with steric shield.
- isoxazoyl ring provides a steric shield and electron-withdrawing group
- steric shield blocks beta-lactamase activity
- oxacillin-resistant S. aureus (ORSA) is categorized as MRSA
Chemistry of Penicillins
What are broad spectrum penicillins?
beta-lactamase-sensitive
- compared to penicillin G (112 Å2), these drugs are more polar
- carboxypenicillins like ticarcillin contain an additional ionizable group – more hydrophilic
- both of these compounds are used parenterally for gram negative infections (ie. P. aeruginosa)
Chemistry of Penicillins
What is the broadest spectrum penicillin?
piperacillin
Chemistry of Penicillins
What do beta-lactamase (suicide substrate) inhibitors do?
broaden the spectrum of penicillins toward gram-negative bacteria (that have weak intrinsic antibacterial activity)
Chemistry of Penicillins
Which antibiotics have weak intrinsic antibacterial activity?
- clavulanic acid
- sulbactam
- tazobactam
Chemistry of Penicillins
What is clavulanic acid?
- mould product
- forms two covalent bonds to target
- added to amoxicillin and ticarcillin preparations
Chemistry of Penicillins
What is the mechanism of inhibition of clavulanic aci?
see notes
- two sites of attachment to the beta-lactamase
Chemistry of Penicillins
What is sulbactam?
- prepared from partial synthesis of penicillin
- sulfone enhances potency against beta-lactamases
- added to ampicillin preparation
Chemistry of Penicillins
What is tazobactam?
- sulfone enhances potency against beta-lactamases
- co-administered with piperacillin or ceftolozan for broadest spectrum beta-lactam antibiotic
Chemistry of Penicillins
What is monobactam?
- parenteral, synthetic monobactam used exclusively for gram-negative organisms (aminothiazole and Z-oxime moieties are common features in 3rd generation cephalosporins)
- sulfamic acid is a strong EWG that makes beta-lactam amide bond more vulnerable to hydrolysis – occupies a similar space as the penicillanic acid carboxyl group
- capable of inactivating some beta-lactamases – methyl substituent is attributed to stability of aztreonam toward beta-lactamases
Chemistry of Penicillins
Demonstrate the chemical basis for penicillin allergenicity.
- primary amino groups from beta-lactam antibiotics and nucleophilic groups from host proteins can contribute to hapten formation (ie. ampicillin dimerization
- cross-reactivity with other beta-lactam antibiotics (cephalosporins and carbapenems) occurs becuase hydrolyzed product forms the common hapten
Chemistry of Penicillins
Identify structural features of penicillin derivatives that mitigate the structure’s acid sensitivity, leading to increased oral bioavailability.
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Chemistry of Penicillins
Identify structural components of some penicillins that prevent susceptibility of hydrolysis from beta-lactamase activity (enzymatic hydrolysis of the beta-lactam ring).
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Chemistry of Cephalosporins
Describe the chemical properties of cephalosporin C.
- cephalosporin C has 1/1000 the activity of penicillin G, but has a much broader spectrum of activity
- dihydrothiazine ring results in decrease in beta-lactam ring strain
- reactivity facilitated by ejection of acetate during the hydrolysis mechanisms to inactivate bacterial transpeptidases
Chemistry of Cephalosporins
What is the problem with cephalosporin C?
How can this issue be addressed?
esterase metabolism of C-3 acetyl moiety leads to lactonization
- eliminate ester and replace with other substituents
Chemistry of Cephalosporins
Describe the spectrum of activity of cephalosporins.
- lower generations are more effective against gram-positive bacteria
- higher generations are more effective against gram-negative bacteria
Chemistry of Cephalosporins
1st Generation Parenteral Agent
cefazolin
- thiadiazole leaving group
Chemistry of Cephalosporins
1st Generation Oral Agent
cephalexin, cefadroxil
- amino groups prevents NGP
- no activating leaving group, so less active (but more orally bioavailable)
- limited gram-negative activity compared to ampicillin and amoxicillin
Chemistry of Cephalosporins
2nd Generation Parenteral Agent
- cefuroxime
- cefotetan
- cefoxilin
Chemistry of Cephalosporins
Cefuroxime
- Z-oxime group reduces beta-lactamase activity
- carbamoyl group exhibits improved stability over classing acetyl leaving group
Chemistry of Cephalosporins
Cefotetan
- MTT prevents metabolism and increases potency, but when released causes prothrombin deficiency, bleeding, antabuse-like acute alcohol intolerance
- methoxy reduces beta-lactamase activity
Chemistry of Cephalosporins
Cefoxilin
- methoxy reduces beta-lactamase activity
Chemistry of Cephalosporins
2nd Generation Oral Agent (2)
- cefaclor
- cefprozil
Chemistry of Cephalosporins
Cefaclor
- isosteric replacement in cephalexin
Chemistry of Cephalosporins
Cefprozil
- 1-propenyl group (trans form) increases potency and spectrum compared to 1st generation analogue cefadroxil
Chemistry of Cephalosporins
3rd Generation Parenteral Agent (2)
- cefotaxime
- ceftriaxone
Chemistry of Cephalosporins
Cefotaxime
- aminothiazole group
- beta-lactamase resistance
- metabolically lavile acetate
Chemistry of Cephalosporins
Ceftriaxone
(best anti-staphylococcal activity among 3rd generation cephalosporins)
- aminothiazole group
- beta-lactamase resistance
- thiotriazenedione
Chemistry of Cephalosporins
3rd Generation Oral Agent (2)
- ceftazidime
- cefixime
Chemistry of Cephalosporins
Ceftazidime
(distinguished among cephalosporins for activity against P. aeruginosa)
- aminothiazole group
- improved beta-lactamase resistance
- pyridinium group for penetration and activity
Chemistry of Cephalosporins
Cefixime
(40-50% absorbed orally)
- aminothiazole group
- improved beta-lactamase resistance
- vinyl group contributes to oral activity
Chemistry of Cephalosporins
4th Generation Parenteral Agent
broadened gram-negative activity and enhanced anti-staphylococcal activity
- cefepime
Chemistry of Cephalosporins
Cefepime
- N-methylpyrrolidinium helps penetration into gram-negative bacteria
Chemistry of Cephalosporins
5th Generation Parenteral Agent
broad spectrum activity and bactericidal against MRSA
- ceftaroline
- ceftobiprole
- ceftolozane
Chemistry of Cephalosporins
Ceftaroline
- N-methylpyridinium helps penetration into gram-negative bacteria
Chemistry of Cephalosporins
Ceftobiprole
- pyrrolidine helps penetration into gram-negative bacteria
Chemistry of Cephalosporins
Describe the chemical properties of the cephalosporanic acid nucleus and compare with the penicillanic acid nucleus.
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Chemistry of Cephalosporins
Show the cephalosporin mechanism of transpeptidase inhibition.
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Chemistry of Cephalosporins
Identify structural features of cephalosporin derivatives that mitigate the structure’s acid sensitivity, leading to increased oral bioavailability.
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Chemistry of Cephalosporins
Identify structural components of some cephalosporins that prevent susceptibility of hydrolysis from beta-lactamase activity.
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Chemistry of Carbapenems
What does thienamycin exhibit resistance to and why?
exhibits some resistance to beta-lactamases purportedly due to the absent acyl amino side chain and the opposite sterochemistry compared to penicillins and cephalosporins
Chemistry of Carbapenems
Describe the features of thienamycin.
- double bond leads to ring strain
- carbapenem nucleus
- carbon atom
- trans-stereo hydrogens
- acyl amino side chain absent
Chemistry of Carbapenems
What prevented thienamycin from being developed for therapeutic use?
instability of this natural product
- ie. intermolecular conjugation of 1º amino group to carbonyl carbon of beta-lactam
Chemistry of Carbapenems
How was the instability of thienamycin addressed?
made a thienamycin analogue called imipenem (N-formimidoylthienamycin)
- N-formiminoyl group decreases nucleophilicity
Chemistry of Carbapenems
What is imipenem?
broader spectrum antibiotic than cephalosporins
Chemistry of Carbapenems
What must occur with imipenem?
must be taken with the renal dehydropeptidase-1 inhibitor cilastatin (1:1 ratio) because the enzyme dehydropeptidase-1 hydrolyzes the beta-lactam ring
Chemistry of Carbapenems
What is cilistatin?
contains several pharmacophoric groups in common with imipenem
Chemistry of Carbapenems
What are some other carbapenems and their features?
meropenem, doripenem, ertapenem
- parenteral agents due to reactivity of beta-lactam ring
- last resort antibiotics because they cause induction of beta-lactamases
- ineffective against MRSA/ORSA
Chemistry of Carbapenems
Meropenem
- chiral methyl group at C-4 confers stability roward dehydropeptidase-1
Chemistry of Carbapenems
Doripenem
- sulfamide group improves activity toward P. aeruginosa
Chemistry of Carbapenems
Ertapenem
- addition of benzoic acid group increases time in circulation
