Structure, Mechanism of action, uses and SAR of Beta-lactam antibiotics

1. Beta-Lactam
Antibiotics
Dr. Gopal Krishna Padhy
Assoc. Professor
Centurion University of Technology and
Management

2.  Paul Ehrlich, a German physician, noted that certain chemical
dyes coloured some bacterial cells but not others.
 He concluded that, according to this principle, it must be possible
to create substances that can kill certain bacteria selectively
without harming other cells.
 In 1909, he discovered that a chemical called arsphenamine was
an effective treatment for syphilis. This became the first modern
antibiotic, although Ehrlich himself referred to his discovery as
'chemotherapy'
 The word 'antibiotics' was first used over 30 years later by the
Ukrainian-American inventor and microbiologist Selman
Waksman, who in his lifetime discovered over 20 antibiotics.
Historical Background

3.  Beta-lactam antibiotics, which are named for the beta-lactam
ring in their chemical structure, include the penicillins,
cephalosporins and related compounds.
 These agents are active against many gram-positive, gram-
negative and anaerobic organisms.
 The beta-lactam antibiotics exert their effect by interfering
with the structural crosslinking of peptidoglycans in bacterial
cell walls.
β-Lactam antibiotics

4. Alexander Fleming accidentally discovered penicillin. 1928, he
noticed that a fungus, Penicillium notatum, had contaminated a
culture plate of Staphylococcus bacteria he had accidentally left
uncovered.
The fungus had created bacteria-free zones wherever it grew on
the plate. Fleming isolated and grew the mould in pure culture.
He found that P. notatum proved extremely effective even at very
low concentrations, preventing Staphylococcus growth even when
diluted 800 times, and was less toxic than the disinfectants used
at the time.
Penicillin

5.  Natural penicillin
IPUPAC: 3,3-dimethyl-7-oxo-6-(2-phenoxyacetamido)-4-thia-1-azabicyclo[3.2.0]heptane-2-
carboxylic acid
Classification
Penicillin V

6. Cl
S
O
HO
O
O
O
N
H
N
N
H
1
2
3
4
5
6
7
Cloxacillin
 Penicillinase-resistant penicillin
Dicloxacillin
S
O
HO
O
O
O
N
H
N
N
H
Oxacillin
(2S,5R,6R)-3,3-dimethyl-6-(5-methyl-3-phenyl-
1,2-oxazole-4-amido)-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid
(2S,5R,6R)-6-[3-(2-chlorophenyl)-5-methyl-1,2-
oxazole-4-amido]-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid
(2S,5R,6R)-6-[3-(2,6-dichlorophenyl)-5-methyl-1,2-
oxazole-4-amido]-3,3-dimethyl-7-oxo-4-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid

7.  Aminopenicillin
S
O
HO
O
O
N
H
N
NH2
H
(2S,5R,6R)-6-[(2R)-2-amino-2-
phenylacetamido]-3,3-dimethyl-7-oxo-4-thia-
1-azabicyclo[3.2.0]heptane-2-carboxylic acid
Ampicillin
Amoxicillin
(2S,5R,6R)-6-[(2R)-2-amino-2-(4-
hydroxyphenyl)acetamido]-3,3-dimethyl-7-oxo-4-
thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid

8.  Bacteria cells are surrounded by a protective envelope called the cell wall. One
of the primary components of the bacterial cell wall is peptidoglycan, a structural
macromolecule with a net-like composition that provides rigidity and support to
the outer cell wall.
 In order to form the cell wall, a single peptidoglycan chain is cross-linked to other
peptidoglycan chains through the action of the enzyme DD-transpeptidase (also
called a penicillin binding protein—PBP).
 Penicillin kills bacteria through binding to DD-transpeptidase, inhibiting its cross-
linking activity and preventing new cell wall formation. Without a cell wall, a
bacterial cell is vulnerable to outside water and molecular pressures, and quickly
dies.
Mechanism of action of Penicillin

10. Uses
Penicillin is effective against Streptococci
(including Streptococcus pneumoniae), Listeria, Neisseria gonorrhoeae,
Clostridium and Peptococcus.
However, most staphylococci now are resistant to penicillin.
penicillin antibiotics are also effective against H. influenzae, E. coli, pneumococci,
certain strains of staphylococci.
Penicillin antibiotics are used to treat many types of infections caused by
susceptible bacteria. They are used to treat infections of the middle ear,
sinuses, stomach and intestines, bladder, and kidney. They also are used for
treating pneumonia, blood infections (sepsis) and uncomplicated gonorrhea.
Adverse effects
 Common adverse drug reactions (≥ 1% of people) associated with use of the
penicillins include diarrhea, hypersensitivity, nausea, rash and neurotoxicity.
 Life threatening effect includes Anaphylaxis and Seizures.

11.  Although the cephalosporins are often thought of as new and improved
derivatives of the penicillins, they were actually discovered as naturally
occurring substances separate from the penicillins.
 It was isolated as a substance with antibacterial properties from
fungus Cephalosporium acremonium.
 The core of the basic cephalosporin molecule consists of a two ring system
which includes a β-lactam ring condensed with dihydrothiazine ring.
Cephalosporins

12. First-generation agents
Classification
Cefadroxil
(6R,7R)-7-[(2R)-2-amino-2-(4-
hydroxyphenyl)acetamido]-3-methyl-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Cephalexin
N
S
H
N
O
O
O OH
NH2
H
(6R,7R)-7-[(2R)-2-amino-2-phenylacetamido]-3-
methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid

13. (6R,7R)-7-[(2R)-2-amino-2-(cyclohexa-1,4-dien-1-
yl)acetamido]-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-
ene-2-carboxylic acid
S
O
O
OH
O
N
H
N
NH2
H
Cephradine

14. Second-generation agents
N
S
H
N
O
O Cl
O OH
NH2
H
Cefaclor
(6R,7R)-7-[(2R)-2-amino-2-phenylacetamido]-
3-chloro-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-
2-ene-2-carboxylic acid
N
S
O
H
N
O
HO
O
NH2
H H
HO CH3
Cefprozil
(6R,7R)-7-[(2R)-2-amino-2-(4-
hydroxyphenyl)acetamido]-8-oxo-3-(prop-1-en-
1-yl)-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid

15. Third-generation agents
Cefixime
(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
[(carboxymethoxy)imino]acetamido]-3-ethenyl-8-oxo-5-thia-1-
azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid
Cefpodoxime
(6R,7R)-7-[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-
(methoxyimino)acetamido]-3-(methoxymethyl)-
8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-
carboxylic acid

16. Mechanism of action of Cephalosporin

17. Some examples of infections that cephalosporins can treat include:
Skin or soft tissue infections
Urinary tract infections (UTIs)
Strep throat
Ear infections
pneumonia
Sinus infections
Meningitis
Gonorrhea
Uses
Adverse effects
Cephalosporins can cause a range of side effects, including:
 Stomach upset
 Nausea
 Vomiting
 Diarrhea
 Dizziness

18.  Beta-lactamases are a family of enzymes involved in bacterial resistance to beta-
lactam antibiotics. They act by breaking the beta-lactam ring that allows penicillin-
like antibiotics to work.
 Drug substance that inhibit the enzyme Beta-lactamases are called beta-lactamase
inhibitors.
 Although β-lactamase inhibitors have little antibiotic activity of their own, they
prevent bacterial degradation of beta-lactam antibiotics and thus extend the range
of bacteria the drugs are effective against.
 They are co-administered with beta-lactam antimicrobials to prevent antimicrobial
resistance.
 Beta-lactamase inhibitors are primarily indicated for infections by gram-negative
bacteria, as they produce this enzyme.
β- Lactamase inhibitors

19. Clavulanic acid
(2R,3Z,5R)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid
Sulbactam
(2S,5R)-3,3-dimethyl-4,4,7-trioxo-thia-1-
azabicyclo[3.2.0]heptane-2-carboxylic acid

20.  Monobactams are monocyclic β-lactam antibiotics. The β-lactam ring is
not fused to another ring, in contrast to most other β-lactams.
 Monobactams are effective only against aerobic Gram-negative
bacteria (e.g., Neisseria, Pseudomonas).
Monobactams
Aztreonam
(2S,3S)-3-[(2Z)-2-(2-azaniumyl-1,3-thiazol-4-yl)-2-[(1-carboxy-
1-methylethoxy)imino]acetamido]-2-methyl-4-oxoazetidine-1-
sulfonate

21. Adverse effects
Include skin rash and occasional abnormal liver functions.
 The antibacterial activity of monobactam is mediated mainly by inhibition of
penicillin binding protein 3 (PBP3), interfering with peptidoglycan synthesis and
cell wall formation
Mechanism of action of monobactam
Uses
 used primarily to treat infections caused by gram-negative bacteria such
as Pseudomonas aeruginosa.
 This may include bone infections, endometritis, intra abdominal infections,
pneumonia, urinary tract infections, and sepsis.

22.  The main cause of deterioration of penicillin is the reactivity of the strained lactam ring,
particularly to hydrolysis.
 The β-lactam carbonyl group of penicillin readily undergoes nucleophilic attack by water or
(especially) hydroxide ion to form the inactive penicilloic acid, which is reasonably stable in
neutral to alkaline solutions but readily undergoes decarboxylation and further hydrolytic
reactions in acidic solutions.
 It has been speculated that one of the causes of penicillin allergy may be the formation of
antigenic penicilloyl proteins in vivo by the reaction of nucleophilic groups (e.g., -amino) on
specific body proteins with the β–lactam carbonyl group.
Degradation of penicillin

23.  Cephalosporins experience various hydrolytic degradation reactions whose specific nature depends on the
individual structure.
 The reactive functionality common to all cephalosporins is the β-lactam. Hydrolysis of the β -lactam of
cephalosporins is believed to give initially cephalosporoic acids.
 The 7-acylamino group of some cephalosporins can also be hydrolyzed under enzymatic (acylases) and, possibly,
nonenzymatic conditions to give 7-Aminocephalosporanic acid (7-ACA) derivatives.
 Following hydrolysis or solvolysis of the 3-acetoxymethyl group, 7-ACA also lactonizes under acidic conditions.
Degradation of cephalosporins

24. SAR of penicillin
The chemical substituents attached to the penicillin nucleus can greatly
influence the stability of the penicillins as well as the spectrum of
activity.
Position-1: If the sulfur atom of the Thiazolidine ring is oxidized to
sulfone or sulfoxide, it improves acid stability, but decrease the activity
of the agent.
Position-2: No substitution allow at this position, any change will lower
activity, Methyl groups are necessary
S
O
HO
O
O
N
H
N
R
H 1
2
3
4
6
7
5
The general structure of penicillin is represented below

25. Position-3: The carboxylic acid of the Thiazolidine is required for
activity. If it is changed to an alcohol or ester, activity is decreased.
Position-4: The nitrogen is must.
Position-5: No substitution allowed.
Position-7: The carbonyl on the beta-lactam ring is must
Position-6: Substitution are allowed on the side chain of the amide.
o An electron withdrawing group added at this position will give the
compound better acid stability because this substitution will make
the amide oxygen less nucleophilic.
o A bulky group added close to the ring will make the compound
more resistant to beta-lactamases by steric hindrance.

26. SAR of cephalosporin
The general structure of cephalosporin is represented below
Position-1: oxidation of the sulfur atom of the dihydrothiazine ring to
sulfone decrease the activity of the agent.
Position-2: No substitution allow at this position, any change will lower
activity.
Position-3: The pharmacokinetic and pharmacodynamics depends on
C-3 substituents. Modification at C-3 position has been made to reduce
the degradation of cephalosporins.

27. Orally active compounds are produced by placement of CH3 and Cl at C-
3 position.
Position-4: The carboxyl group at position-4 can be converted into ester
prodrugs to increase bioavailability of cephalosporins, and these can be
given orally as well.
Position-5: The nitrogen is must.
Position-6: No substitution allowed.
Position-8: The carbonyl on the beta-lactam ring is must
Position-7: Substitution are allowed on the side chain of the amide.
e.g. phenyl group

28.  The addition of amino group at α position produces basic
compound, which is protonated under acidic conditions of stomach.
The ammonium ion improves the stability of β-lactam of
cephalosporins and make orally active compound.
 Substitutions on the aromatic phenyl ring increase lipophilicity and
provide higher gram-positive activity and generally lower gram-
negative activity.
 The phenyl ring in the side chain can be replaced with other
heterocycles with improved spectrum of activity and
pharmacokinetic properties; these include thiophene, tetrazole,
furan, pyridine, and aminothiazoles.