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Patrick

An Introduction to Medicinal Chemistry 3/e

Chapter 19

ANTIBACTERIAL AGENTS

Part 3: Other lactams

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Carbapenems

• Thienamycin

• Imipenem

• Meropenem

• Ertapenem Core structure of the carbapenem molecules

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Oppositestereochemistry to penicillins

Newer β-Lactam Antibiotics

Thienamycin (Merck 1976) (from Streptomyces cattleya)

• 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)

CarbonPlays a rolein ß-lactamaseresistance

O

N

S

OH

H3C

CO2

H

NH3

H

Double bond leading to high ring strain and an increasein -lactam ring reactivity

Acylamino sidechain absent

Carbapenam nucleus

S

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Newer β-Lactam Antibiotics

Thienamycin analogues used in the clinic

NO

H

S

HN

CO2

OH

Me

HNH

Imipenem

aminomethylideneamino

1. Produced by the bacteria Streptomyces

cattleya .

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.

N-Formimidoyl derivative of

thienamycin

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Imipenem

dehydropeptidase

metabolites

DHP= dehydropeptidases

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Meropenem (Merrem) MEROTROL

NO

H

S

CO2

OH

Me

H

HN C

N

O

Me

Me

H

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

pyrrolidin-2-yl-sulfanyl

Carbapenam nucleus

CH3

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Meropenem MEROTROL

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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 anaerobic bacteria.

pyrrolidin-2-yl-sulfanyl

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Doribax (Doripenem)

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Doripenem and Ertapenem

(A) The structures of Doripenem and Ertapenem. (B) The chemical mechanism

of hydrolysis of Ertapenem by the Mycobacterium tuberculosis BlaC.

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Stability toward

dehydropeptidase

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Carbapenems

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Newer β-Lactam Antibiotics

Monobactams

• Monocyclic β-Lactams:

–Nocaridicin

–Aztreonam

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Newer β-Lactam Antibiotics

Nocardicins (Fujisawa 1975)

• 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

Nocardicin A

DCO

N

CHN

H

N

C

CO2H

O

OH

CH2CH2 OHHC

HO2C

H2N

H

O

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Newer β-Lactam Antibiotics

Clinically useful monobactam

• 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

Aztreonam N

O

HN

O

SO3-

Me

NO

CO2HMeMe

N

S

H2N

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β-Lactamase Inhibitors

Clavulanic acid (Beechams 1976) (from Streptomyces clavuligerus)

• 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

No acylaminoside chain

Sulphur replaced by O

-Lactam

9

2

53

4

17

6

H

CO2H

O

N

OH

OH

H

Acyl side

chain

-Lactam

ring

Thiazolidine

ring

N

S Me

Me

HN

H H

CO2HO

C

O

R

Oxazolidine ring

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2

N H 2

CH2OHO

HN

O

O

CO2H

BaseH

Clavulanic acid - mechanism of action

O H

N H 2

1

H

5

NH

CH

O

HC

O

Irreversibly blocked

4

H

CH2OH

CO2H

O

O

H2N

O

NH

3

CH2OH

CO2H

O

O

HN

O

NH

H

β-Lactamase Inhibitors

C H 2 O H

C O 2 H

O

N

O

OH

O

NH2

HO

O

2-Amino-5-hydroxy-3-oxopentanoic acid

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Clavulanic acid NXL104

Avibactam (NXL104)

NXL104

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Penicillanic acid sulfone derivatives

• 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

β-Lactamase Inhibitors

N

O

S

CO2

OO

Me

Me

Na

N

O

S

CO2

OO

Me

N

NN

1

2

3

56

7

6

3

Sulbactam Tazobactam

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Olivanic Acids

MM 13902

Naturally occurring carbapenem -lactamase inhibitors with

antibacterial activity, produced by Streptomyces olivaceus

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NH2H3C

OOH

L-Alanine

NH2H3C

OOH

D-Alanine

RacemaseHN O

HO

NH2

O

D-Alanine-D-Alanine

D-Ala-D-Ala

Ligase

X

• 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)

X

Used in the treatment of tuberculosis

D-4-amino-3-isoxazolidone

D-Cycloserine

Other drugs which act on bacterial cell wall biosynthesis

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D-AlanineTRANSPEPTIDASE

PENICILLIN

SUGARBACKBONE

NAM

L-Ala

NAG

D-Glu

L-Lys

D-Ala

D-Ala

Gly Gly Gly Gly Gly Gly GlyGlyGlyGlyL-Lys

NAG

D-Ala

D-Ala

D-Glu

L-Ala

NAM

SUGARBACKBONE

L-Lys Gly Gly

D-Ala

NAM

L-Ala

NAG

D-Glu

L-Lys Gly Gly Gly Gly GlyGlyGlyGly

NAG

D-Ala

D-Glu

L-Ala

NAM

Cross linking

Mechanism of action - bacterial cell wall synthesis

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Glycopeptides: VANCOMYCIN FAMILY

Isolated

Streptomyces orientalis

Used in the prophylaxis and treatment of infections caused by Gram-

positive bacteria (narrow-spectrum bactericidal glycopeptide)

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Crystal structure

• 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.

James R. Knox and R. F. Pratt in Antimicrobial Agents and Chemotherapy, Year 1990, Volume

34, Issue 7, Pages 1342-1347.

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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

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Capping Mechanism

Transglycosylation

The transfer of a sugar residue from

one glycoside to another (bond

formation, particularly during

polysaccharide synthesis)

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Dimerization of VANCOMYCIN

4 H-Bonds

5 H-Bonds

5 H-Bonds

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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 units then

complete the structure

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Resistance to VANCOMYCIN

Vancomycin does not bind to D-Ala-D-Lac, which

leads to vancomycin resistance

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.

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β-D-glucosamine

Teicoplanins: Mixture of 5 major

constituents and four minor (named

Teicoplanin RS-1 through RS-5)

Th e teicoplanins belong to the vancomycin

family but do not dimarize

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Teicoplanin-A2-5

• 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.

Its mechanism of action

is to inhibit bacterial

cell wall synthesis.

Teicoplanin is marketed

by Aventis under the

trade name Targocid®.

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Binding Mode of Teicoplanin

Teicoplanins belong to the vancomycin family but do not dimarize.

The long alkyl chain plays an importart 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.

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Eremomycin and Y33328

LY33328 is 1000 times > active than vancomycin

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Removal of a tetrahydropyran ring to leave an alcohol group (R 4 ),

modification of the hydrophobic tail (R 2 ) and addition of a side

chain with a phosphate group (R 3 ), to give telavancin , which was

approved in 2009.

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Simplification of Natural Products

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

Simplified

analogues of

the

glycopeptides

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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.

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Bacitracin

• 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

• 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.

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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.