Beta Lactam Antibiotics
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Transcript of Beta Lactam Antibiotics
Beta Lactam Antibiotics
Presentation by:Saurav Chandra SarmaInt. Ph.D NCU 3rd Sem.
Outline
1• What is Antibiotic???
• Bacterial cell structure
2
• Beta-lactam Antibiotics and it’s mode of action
• Resistance to Beta lactam Antibiotics
• Examples
3
• Beta-lactamases and its classification
• Proposal
• Conclusion.!!!
Antibiotics and it’s Classification
Antibiotics
•An antibiotic is an agent that either kills or inhibits the growth of a microorganism.
•Excludes substances that kill bacteria but that are not produced by microorganisms such as Gastric juices & Hydrogen Peroxide.
•Also excludes synthetic antibacterial compound such as sulfonamides.
•Penicillin is the first natural antibiotic discovered by Alexander Fleming in 1928.
Classification of Antibiotics
Based on mode of Action
Bacteriostatic Bactericidal
Based on their spectrum of
action
Broad-spectrumNarrow
Spectrum
Source: Google Images
Types of Antibiotics(Based on their mode of action)
Bacteriostatic Antibiotics
• Tetracyclines
• Spectinomycin
• Sulphonamides
• Macrolides
• Chloramphenicol
• Trimethoprim
Bactericidal Antibiotics
• Penicillins
• Cephalosporins
• Fluoroquinolones(Ciprofloxacin)
• Glycopeptides (Vancomycin)
• Monobactams
• Carbapenems
Types of Antibiotics(Based on their structural similarities)
Antibiotics: Mode of Action
•Inhibitors of DNA synthesis
•Inhibitors of bacterial protein synthesis
•Inhibitors of bacterial cell wall synthesis
•Interference with metabolism
•Impairment of nucleic acids
Antibiotic Targets
Sourcs: Microbiology: A Clinical Approach
Bacterial Cell structure
Gram positive vs. Gram negative bacteria
Source: Google Images
Cell Wall
Source: Google Images
Structure of Peptidoglycan layer
•Peptidoglycan is a carbohydrate composed of alternatingunits of NAMA and NAGA.
•The NAMA units have a peptide side chain which can becross linked from the L-Lys residue to the terminal D-Ala-D-Ala link on a neighboring NAMA unit.
Source: Google Images
Transpeptidase Enzyme
•The cross linking reaction is catalyzedby a class of transpeptidases known aspenicillin binding proteins
•A critical part of the process is therecognition of the D-Ala-D-Alasequence of the NAMA peptide sidechain by the PBP. Interfering with thisrecognition disrupts the cell wallsynthesis.
•β-lactams mimic the structure of theD-Ala-D-Ala link and bind to the activesite of PBPs, disrupting the cross-linking process.
Source: Google Images
Transpeptidation mechanism
Source: Google Images
Transpeptidation mechanism
Source: Google Images
Beta–lactam Drugs
Beta-Lactam Antibiotics
β-lactam ring
•Contains a beta-lactam ring in their molecular structures.
•Nitrogen is attached to the beta carbon relative to the carbonyl ring and hence the name.
Classification
•Penicillins
•Cephalosporins
•Other β-Lactam drugs
--Cephamycins--Carbapenems--Oxacephalosporins--β-Lactamase inhibitors--Monolactams
Beta-Lactam Structure
How do they work?
1. The β-lactam binds to Penicillin Binding Protein (PBP)
2. PBP is unable to crosslink peptidoglycanchains
3. The bacteria is unable to synthesize a stable cell wall
4. The bacteria is lysed
Mechanism of β-Lactam Drugs
• The amide of the β-lactam ring is unusuallyreactive due to ring strain and a conformationalarrangement which does not allow the lone pair ofthe nitrogen to interact with the double bond ofthe carbonyl.
• β-Lactams acylate the hydroxyl group on the serineresidue of PBP active site in an irreversible manner.
• This reaction is further aided by the oxyanion hole,which stabilizes the tetrahedral intermediate andthereby reduces the transition state energy.
Discovery of Penicillin(First beta-lactam drug)
•Discovered in 1928.
• While working in his lab, trying to kill a deadly bacteria,he noticed a
blue mold growing on the dish
•Learned that it was the mold Penicillum Notatum.
•Penicillin is found in this mold.
•Noticed that the bacteria around the mold was dissolving.Source: Google Images
How it is was Developed
• For 9 years, nobody could purify the Penicillum Notatumto get the pure penicillin.
Finally, in 1938, a team of Oxford University Scientists, headed by Howard Florey and Ernst B. Chain helped to develop penicillin.
Source: Google Images
Mechanism of β-Lactam Drugs
• The amide of the β-lactam ring is unusually reactive due to ring strain and a conformational arrangement which does not allow the lone pair of the nitrogen to interact with the double bond of the carbonyl.
• β-Lactams acylate the hydroxyl group on the serine residue of PBP active site in an irreversible manner.
• This reaction is further aided by the oxyanion hole, which stabilizes the tetrahedral intermediate and thereby reduces the transition state energy.
Mechanism of β-Lactam Drugs
The hydroxyl attacks the amide and forms a tetrahedral intermediate.
Mechanism of β-Lactam Drugs
The tetrahedral intermediate collapses, the amide bond is broken, and the nitrogen is reduced.
Mechanism of β-Lactam Drugs
The PBP is now covalently bound by the drug and cannot perform the cross linking action.
Penicillin
Natural Penicillin
Penicillin V (Phenoxymethylpenicillin)
EFFECTIVE AGAINST:
• Gram positive + Less effective against Gram negative bacteria
TREATMENT FOR:
• Tonsillitis
• Anthrax
• Rheumatic fever
• Streptococcal skin infections
CHARACTERISTICS:
• Narrow spectrum
• Should be given orally
• Prone to beta-lactamase
Penicillin V (Phenoxymethylpenicillin)
EFFECTIVE AGAINST:
• Gram positive + Less effective against Gram negative bacteria
TREATMENT FOR:
• Tonsillitis
• Anthrax
• Rheumatic fever
• Streptococcal skin infections
CHARACTERISTICS:
• Narrow spectrum
• Should be given orally
• Prone to beta-lactamase
Amino-Penicillin
Ampicillin R=Ph
Amoxicillin R= Ph-OH
Ampicillin
EFFECTIVE AGAINST:• Gram positive + Gram negative
bacteriaTREATMENT FOR:• Ear infection• Sinusitis• Urinary tract infections• MeningitisCHARACTERISTICS:• Broad spectrum• Can be given orally and
parenterally• Prone to beta-lactamase
Ampicillin
Sulbactam
+
llUnasyn
Amoxicillin
EFFECTIVE AGAINST:• Gram positive + Gram negative
bacteriaTREATMENT FOR:• Skin infection• Sinusitis• Urinary tract infections• Streptococcal pharyngitisCHARACTERISTICS:• Broad spectrum• Can be given orally and parenterally• Prone to beta-lactamaseSIDE-EFFECTS:• Rash, diarrhea, vomiting, nausea,
edema, stomatitis, and easy fatigue.
Amoxicillin
Clavulanic Acid
+
ll
Augmentin
Anti-Staphylococcal Penicillin
Methicillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT FOR:
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Interstitial nephritis
Oxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT AGAINST:
• penicillin-resistant Staphylococcus aureus
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Hypersensitivity and local reactions
• In high doses, renal, hepatic, or nervous system effects can occur
Nafcillin
EFFECTIVE AGAINST:
• Gram positive bacteria
TREATMENT AGAINST:
• Staphylococcal infections
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given parenterally
SIDE-EFFECT:
• Allergic reactions
• Nausea and vomiting
• Abdominal pain
Cloxacillin
EFFECTIVE AGAINST:
• Staphylococci that produce beta-lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
Dicloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria + Staphylococci that produce beta-lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
• Diarrhoea, nausea, rash, urticariapain and inflammation at injection site
Flucloxacillin
EFFECTIVE AGAINST:
• Gram positive bacteria + Staphylococci that produce beta-lactamase
CHARACTERISTICS:
• Very narrow Spectrum
• Should be given orally
SIDE-EFFECT:
• Allergic reaction
• Diarrhoea, nausea, rash, urticariapain and inflammation at injection site
Anti-Pseudomonal Penicillin
Piperacillin
EFFECTIVE AGAINST:
• Gram positive +Gram negative
CHARACTERISTICS:
• Extended Spectrum
• Should be given by intravenous or intramuscular injection
SIDE-EFFECT:
• Hypersensitivity
• Gastrointestinal
• Renal
• Nervous system
*Piperacillin+Tazobactam=Zosyn
Carbenicillin
EFFECTIVE AGAINST:
• Gram negative + Limited Gram positive
TREATMENT FOR:
• Urinary tract infections
CHARACTERISTICS:
• Highly soluble in water and acid-labile
SIDE-EFFECT:
• High doses can cause bleeding
• Hypokalemia
Ticarcillin
EFFECTIVE AGAINST:
• Mainly gram negative bacteria particularly Pseudomonas aeruginosa
TREATMENT FOR:
• Stenotrophomonas maltophiliainfections
CHARACTERISTICS:
SIDE-EFFECT:
• Diarrhoea
• Bleeding
• Fever
• Fainting
Cephalosporin
These has been conventionally classified into four generations based on Generation system
• This is based on chronological sequence of development, but more importantly ,takes into consideration the overall antibacterial spectrum as well as potency.
• First-generation cephalosporins are predominantly active against Gram-positive bacteria, and successive generations have increased activity against Gram-negative bacteria (albeit often with reduced activity against Gram-positive organisms).
First Generation Cephalosporins
Cefalothin Cefalexin
Cefadroxil Cefazolin
Second Generation Cephalosporins
Cefuroxime(Oral) Cefotetan
Third Generation Cephalosporins
Cefotaxime Ceftriaxone
Ceftazidime
Fourth Generation Cephalosporins
Cefepime
Carbapenem
What are carbapenems
• Carbapenems are a class of beta-lactam antibiotics with a broad spectrum of antibacterial activity. They have a structure that renders them highly resistant to beta-lactamases. Carbapenem antibiotics were originally developed from thienamycin, a naturally-derived product of Streptomycescattleya.
57Dr.T.V.Rao MD
Carbapenems common uses
• Imipenem– Broad spectrum, covers Gram-positive, Gram-negative
(including ESBL-producing strains), Pseudomonas and anaerobes
• Meropenem– Less seizure-inducing potential, can be used to treat CNS
infections
• Ertapenem– Lacks activity vs. Acinetobacter and Pseudomonas
– Has limited activity against penicillin-resistant pneumococci
58Dr.T.V.Rao MD
Imipenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram positive and gram negative bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamaseenzymes
SIDE-EFFECT:
• Seizuregenic at high doses
Meropenem
EFFECTIVE AGAINST:
• Aerobic and anaerobic, Gram positive and gram negative bacteria
CHARACTERISTICS:
• Ultra Broad Spectrum
• Intravenous
• Resistant to beta-lactamaseenzymes
SIDE-EFFECT:
• Diarrhoea
• Vomiting
• headache
Ertapenem
EFFECTIVE AGAINST:
• Gram positive and gram negative bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamaseenzymes
• Not active against MRSA
SIDE-EFFECT:
• Convulsions
• Seizures
• headache
Monobactam
Aztreonam
EFFECTIVE AGAINST:
• Gram positive +Gram negative+Anaerobic bacteria
CHARACTERISTICS:
• Broad Spectrum
• Intravenous
• Resistant to beta-lactamaseenzymes
• Not active against MRSA
SIDE-EFFECT:
• Diarrhoea
• Nausea
• Vomiting
BETA-LACTAMASE INHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» Clavulanic Acid
» Sulbactam
» Tazobactam
Beta–lactam Resistance
Resistance-The Global Battle.!!!
What is Resistance?
•Drug resistance refers to unresponsiveness of a microorganism to an antimicrobial agent.
•Drug resistance are of two types:---Natural Resistance---Acquired Resistance
Natural Resistance:
•Some microbes have always been resistant to certain anti-microbial agent.•They lack the metabolic process or the target side thai is affected by particular drug.
E.g: Gram negative bacilli are normally unaffected by Penicillin G.M. tuberculosis is insensitive to Tetracyclines.
•This type of resistance does not pose significant clinical problem.
Acquired Resistance:
•It is the development of resistance by an organism which was sensiive before due to the use of antimicrobial agent over a period of time.•This can happen with any microbe and is a major clinical problem.However, the development of resistance is dependent on the microorganism as well as the drug.
Porins
Altered penicillin binding proteins
b-lactamases
MECHANISMS OF RESISTANCE
MECHANISMS FOR ACQUIRING
RESISTANCE
69
CHALLENGES OF b-LACTAMASES
1940 : Introduction of penicillins
1940 : First description of b-lactamases published
1944 : Strains of staphylococcus aureus producing
b-lactamase
1960s : Clinical use of expanded spectrum penicillins
- such as ampicillin and carbenicillin
1970s : plasmid mediated b-lactamases assumed prominence in
enterobacteriaceae and gram-negative bacteria
1980-90 : Development of broad-spectrum cephalosporins, cephamycins,
monobactams and carbapenems
1990 : Increased resistance among gram-negative bacteria with inducible
chromosomally-mediated b lactamases
JAC (1993); suppl A: 1-8
Beta–lactamases
Beta-Lactamase Enzyme
Functional Classification
Group 1 (Cephalosporinases*)
Group 2 (Penicillinases,
Cephalosporinases)
Group 3 (Metalloenzymes*)
Group 4 (Penicillinases*)
* Not inhibited by Clavulanic Acid
Beta-Lactamase Enzyme
Molecular Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B
Beta-Lactamase Enzyme
Molecular Classification
Serine Based
Class A Class C Class D
Metallo
B-lactamases
Class B
ESBLs are enzymes that mediate resistance to extended-spectrum (third generation) cephalosporins (e.g., ceftazidime, cefotaxime, and ceftriaxone) and monobactams (e.g., aztreonam) but do not affect cephamycins(e.g., cefoxitin and Cefotetan) or carbapenems(e.g., meropenem or imipenem).
Extended spectra Beta-Lactamase(ESBL)
WHY SHOULD WE DETECT THESE ENZYMES?
• The presence of an ESBL-producing organism in a clinical infection can
result in treatment failure if one of the above classes of drugs is used.
• ESBLs can be difficult to detect because they have different levels of
activity against various cephalosporins. Thus, the choice of which
antimicrobial agents to test is critical. For example, one enzyme may
actively hydrolyze ceftazidime, resulting in ceftazidime minimum
inhibitory concentrations (MICs) of 256 µg/ml, but have poor activity on
cefotaxime, producing MICs of only 4 µg/ml.
• If an ESBL is detected, all penicillin's, cephalosporins, and aztreonam
should be reported as resistant, even if in vitro test results indicate
susceptibility
RISK FACTORS FOR ESBL INFECTION
• Length of hospital stay
• Severity of illness
• Time in the ICU
• Intubation and mechanical ventilation
• Urinary or arterial catheterization
• Previous exposure to antibiotics
Metallo Beta-lactamase
• Resistant against broad spectrum of beta-lactam antibiotics
• These include the antibiotics of the carbapenem family.
• This class of β-lactamases is characterized by the ability to
hydrolyze carbapenems and by its resistance to the
commercially available β-lactamase inhibitors but susceptibility
to inhibition by metal ion chelators.
• The most common bacteria that make this enzyme are Gram
negative such as Escherichia coli and Klebsiella pneumoniae ,
Pseudomonas aeroginosa.
BETA-LACTAMASE INHIBITORS
• Resemble β-lactam antibiotic structure
• Bind to β-lactamase and protect the antibiotic from destruction
• Most successful when they bind the β-lactamase irreversibly
• Three important in medicine:
» Clavulanic Acid
» Sulbactam
» Tazobactam