Download Inhibition of cell wall synthesis

Antibacterial Agents
Doç Dr Nevriye Gönüllü
Antibacterial Agents
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Mechanisms of action
Antibacterial spectrum
Common mechanisms of resistance
Antibacterial agents
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Sulfonamide – the year 1935 (protosil)
Penicillin (Flemming)
Streptomycin
Tetracyclin
................and many others
Despite the rapidity of the introduction of
new chemotherapeutics
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Development of resistance!!!
In vitro antimicrobial
susceptibility testing
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Selects the active chemotherapeutic
agent
Antibacterial spectrum
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Range of activity of an antimicrobial
against bacteria
Broad spectrum: inhibits a wide variety
of gram-positive and gram-negative
bacteria
Narrow spectrum: active against a
limited variety of bacteria
Antibiotic combinations
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To broaden the spectrum for empirical
therapy or treatment of polymicrobial
infections
To prevent the emergence of resistant
microorganisms
To achieve a synergistic killing effect
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Bacteriostatic activity: inhibition of
growth
Bacteriocidal activity:killing of
microrganisms
Antibiotic synergism
Antibiotic antagonism
Inhibition of cell wall synthesis
Beta-lactam antibiotics
Vancomycin
Bacitracin
Inhibition of cell wall synthesis
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Antimycobacterial agents:
Isoniazid
Ethambutol
Cycloserine
Ethionamide
Beta-lactam antibiotics
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Penicillins
Cephalosporins
Cephamycins
Carbapenems
Monobactams
Beta-lactam antibiotics
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Major structural component of bacterial
cell wall is peptidoglycan
Basic structure : alternating molecules
of N-acetylglucosamine and Nacetylmuramic acid cross-linked with
peptide bridges
Peptidoglycan
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Building of this chain and cross-links
catalized by spesific enzmes:
transpeptidases, carboxypeptidases and
endopeptidases
These enzymes are called penicillinbinding proteins (PBPs) because they
can be bound by beta-lactam antibiotics
Beta-lactam antibiotics
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Bind to PBPs in the growing bacterial
cell wall
Bactericidal
Resistance to beta-lactam
antibiotics
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Prevention of interaction between the
antibiotic and the target PBP
Decreased binding of the antibiotic to
the PBP
Hydrolysis of the antibiotic by betalactamases
Resistance to beta-lactam
antibiotics
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Prevention of interaction between the
antibiotic and the target PBP:
Only in gram-negative bacteria
(Pseudomonas species)
Size or charge change in the outer
membrane pores
Resistance to beta-lactam
antibiotics
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Decreased binding of the antibiotic to the
PBP:
Modified PBP that fails to bind beta-lactam
antibiotic but contributes to the synthesis of
peptidoglycan
Streptococcus pneumoniae: modification of
an existing PBP through recombination –
resistant to penicillins
Staphylococcus aureus : acquisition of a new
PBP (e.g., methicillin resistance in
Staphylococcus aureus
Resistance to beta-lactam
antibiotics
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Beta-lactamase production:
More than 200
Some are spesific( penisillinases,
cephalosporinases)
Some have broad range of activity (extendedspectrum beta-lactamases (ESBLs):
commonly encoded on plasmids, easily
transferred, limit the empirical use of betalactam antibiotics
Penicillins
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Highly effective antibiotics with
extremely low toxicity
Obtained from culture of the mold
Penicillium
Penicillins
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Natural penicillins
Penicillin G (IV), penicillin V(oral)
Active against all beta-hemolytic and
most other streptococci,
meningococci,most gram-positive
anaerobes
Penicillins
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Penicillinases resistant penicillins
Nafcillin
Methicillin
Oxacillin
Cloxacillin
Dicloxacillin
+enhanced activity against staphylococci
Penicillins
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Extended spectrum penicillins
Ampicillin
Amoxicillin
Carbenicillin
Ticarcillin
Mezlocillin
Piperacillin
Penicillins
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Extended spectrum penicillins
Ampicillin:spectrum activity limited to
Escherichia, Proteus and Haemophilus
Carbenicillin
Ticarcillin
Piperacillin: Klebsiella, Enterobacter,
Pseudomonas
Beta-lactamase inhibitors
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Clavulanic acid
Sulbactam
Tazobactam
Relatively inactivate by themselves
Combined with penicillins are effective
against beta-lactamase producing
bacteria
Beta-lactamase inhibitors
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Amoxicillin/Clavulanic acid
Ampicillin/Sulbactam
Ticarcillin/Clavulanic acid
Piperacillin/Tazobactam
Cephalosporins and
Cephamycins
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Beta-lactam antibiotic
Isolated first from a mold Cephalosporium
Cephamycins more stable to hydrolysis by
beta-lactamase
Same mechanism as penicillins
Wider antibacterial spectrum
Resistant to many beta-lactamases
Improved pharmacokinetic properties
Cephalosporins
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Narrow spectrum
Expanded spectrum
Broad spectrum
Extended spectrum
Cephalosporins
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Narrow spectrum:1. generation
Cephalexin, cephalothin, cefazolin,
cephapirin, cephradine)
Equivalent activity as oxacillin against
gram-positive some gram-negative
activity (E. coli, Klebsiella, P. mirabilis)
Cephalosporins
Expanded spectrum: 2. generation
„ Cefaclor, cefamandole,cefuroxime,
cefotetan, cefoxitin)
„ Equivalent activity as oxacillin against
gram-positive
„ Improved gram negative activity
including Enterobacter, Citrobacter,
Proteus species
Cephalosporins
Broad spectrum: 3. generation
„ Cefixime, cefotaxime, ceftazidime,
ceftriaxone
„ Equivalent activity as oxacillin against
gram-positive
„ Improved gram negative activity
including Pseudomonas
Cephalosporins
Extended spectrum: 4.generation
„ Cefepime,cefpirome
„ Equivalent activity as oxacillin against
gram-positive
„ Improved gram negative activity
Other beta-lactam antibiotics
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Carbapenems
Monobactams
Carbapenems
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Imipenem
Meropenem
Broad spectrum
Most aerobic and anaerobic gram-positive
and gram-negative bacteria
Except oxacillin-resistant staphylococci, most
Enterococcus faecium, selected gramnegative bacilli (Burkholderia,
Stenotrophomonas, some Pseudomonas)
Monobactam
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Aztreonam
Narrow spectrum
Active against gram negative bacteria
Advantage: do not disturb patient’s
normal flora
Glycopeptides
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Vancomycin
Obtained from Streptomyces
Disrupts cell wall
Active against oxacillin-resistant
Staphylococci and other gram-positive
bacteria resistant to beta-lactam
antibiotics
Vancomycin
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Inactive against gram-negative bacteria
Too large to pass the outer membrane
Intrinsic resistance: Leuconostoc,
Lactobacillus, Pediococcus,
Erysipelothrix and enterococci
Enterococci resistance: plasmids
Polypeptides
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Bacitracin
Isolated from Bacillus
Used in topically applied products skin
infections caused by Staphylococcus and
group A Streptococcus
Gram negative are resistant
Inhibits cell wall synthesis (inhibits
peptidoglycan carrier), may also damage
cytoplasmic membrane and inhibit RNA
transcription
Bacitracin
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Resistance is most likely due to failure
of the antibiotic to penetrate into the
bacterial cell
Polymixins
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Derived from Bacillus
Serious side effects: nephrotoxicity
External treatment of localized infections
Eye infections, external otitis, skin infections
Inactive against gram-positive bacteria
because they have no outer membrane
Oral administration is used to sterilize the
gut.
Antimycobacterial agents:
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Isoniazid
Ethambutol
Cycloserine
Ethionamide
Resistance may be due to reduced drug
uptake or alteration of the target cell
Inhibition of Protein Synthesis
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Aminoglycoside
Tetracycline
Oxazolidinone
Macrolide
Clindamycin
Streptogramin
Aminoglycosides
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From Streptomyces species:
Streptomycin, Neomycin, Kanamycin,
Tobramycin
From Micromonospora: Gentamycin,
sisomicin
Synthetic: Amikasin and Netilmicin
Aminoglycosides
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Irreversibly bind to the 30S ribosomal
proteins
Bactericidal
Anaerobes, streptococci and enterococci
are resistant, aminoglycosides fail to
penetrate through the cell wall
Aminoglycosides
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Primarily used to treat infections with
gram-negative bacilli,tobramicin slightly
more active than gentamisin vs.
Pseudomonas, amikacin most active
Streptomycin : tuberculosis, tularemia
Resistance to Aminoglycosides
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Mutation of the ribosomal binding site
Decreased uptake
Increased expulsion
Enzymatic modification of the antibioticthe most common
Tetracyclines
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Broad spectrum
Inhibition of protein synthesis
Tetracycline, doxycycline,minocycline
Chlamydia, Mycoplasma and Rickettsia
infections
Macrolides
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Broad spectrum
Erythromycin,Clarithromycin,
Azithromycin
Neisseria, Legionella, Mycoplasma,
Chlamydia, Chlamydophila, Treponema,
Rickettsia
Binding to the 23S RNA of the 50S
ribosomal subunit
Oxazolidinone
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Protein synthesis inhibitor
Narrow spectrum
Linezolid
Staphylococci,streptococci, enterococci(
including resistant strains to
penicillins,vancomycin,aminoglycosides)
Chloramphenicol
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Protein synthesis inhibitor
Broad antibacterial spectrum
Drug of choice for typhoid fever
Side effect: bone marrow supression
Plasmid encoded resistance (producing
of chloramphenicol acetyltransferase)
Clindamycin
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Protein synthesis inhibitor (50S
ribosome)
From Streptomyces species
Active against staphylococci and
anaerobic gram-negative bacteria
Cross resistance with erythromycin
occurs
Streptogramins
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From Streptomyces
Protein synthesis inhibitor
Quinupristin-dalfopristin (Synercid)
Use is restricted to vancomycinresistant E faecium
Inhibition of Nucleic Acid
Synthesis
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Quinolones
Rifampin and Rifabutin
Metronidazole
Quinolones
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Synthetic chemotherapeutics
Inhibit bacterial DNA gyrases required
for DNA replication, recombination and
repair
Narrow spectrum
Broad spectrum
Expanded spectrum
Quinolones
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Narrow spectrum:
Nalidixic acid: used in urinary tract
infections
Resistance developed
Quinolones
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Broad spectrum:
Ciprofloxacin, levofloxacin,
lomefloxacin, norfloxacin, ofloxacin
Quinolones
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Expanded spectrum:
Gatifloxacin, grepafloxacin,
clinafloxacin, moxifloxacin)
Broad spectrum especially against
gram-positive bacteria (streptococci and
enterococci)
Resistance to quinolones
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Chromosomally mediated: mutations in
the structural genes for DNA gyrase and
topoisomerase type IV
Rifampin
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Bactericidal for Mycobacterium
tuberculosis
Resistance develops quickly
Should be used as combination
Rifabutin-a derivative: M. avium
Metronidazole
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Amoebiasis
Giardiasis
Serious anaerobic bacterial infections
(including Bacteroides fragilis)
Antimetabolites
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Sulphonamides
Competes with p-aminobenzoic acid
Prevents folic acid synthesis required by
certain microorganisms
Broad spectrum: Nocardia, Chlamydia,
Some protozoa
Antimetabolites
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Trimethoprim: another antimetabolite
+sulfamethoxazole: synergistic
combination
Broad spectrum
Pneumocystis carinii
Resistance to antimetabolites
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Pseudomonas-permeability barriers
Enterocoocci-intrinsic resistance
Other antibiotics
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Clofazidime: M tuberculosis
Pyrazinamide (PZA): M. tuberculosis
Resistance
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1-Genetic bases of resistance
2-Biochemical mechanism of resistance
1-Genetic basis of resistance
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Mutation of cellular genes
Acquisition of resistance genes
Mutation of acquired genes
Biochemical mechanism of
resistance
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Modification of the antibiotic: such as
beta-lactamases
Modification of the target molecule
Restricted access to the target
Efflux pumps