ppt antibacterials Flashcards
was the first person to observe bacteria
Antonie van Leeuwenhoek
“microorganisms are responsible for
diseases”
Louis Pasteur
germ theory of disease, carbolic acid
Joseph Lister
Koch’s postulates
- The microorganism must be present in every case of disease
but absent from healthy microorganism - The suspected microorganism must be isolated and grown in pure culture
- The same disease must result when the isolated microorganism
is inoculated in a healthy host - The same microorganism must be isolated again form the diseased host
* TB, cholera, typhoid
Father of Chemotherapy
* Magic bullet, chemotherapeutic index → therapeutic index
salvarsan (arsphenamine)
Paul Ehrlich
serendipitous discovery
of penicillin
Alexander Fleming
Penicillin as medical treatment
Freeze drying & chromatigraphy
Howard Florey and Boris Ernst Chain
Streptomycin discovery
Selman Waksman
“.. a substance produced by
microorganisms, which have the capacity of inhibiting the growth and even of destroying other microorganisms.”
-S. Waksman
May also be synthesized
Antibiotics
Attributes of antibiotics
*Selective toxicity
*Chemically stable
*Acceptable rate of biotransformation
Antibiotics
Other applications
*Antineoplastic/anti-cancer
*Feed supplements
*Plant antibiotic
*Food preservation
Antibiotics Commercial Preparation
- Preparation of pure culture of microorganism source
- Fermentation
- Isolation of antibiotic
- Purification
- Assays
- Formulation
target: cell wall synthesis
penicillins
cephalosporins
glycopeptides
carbapenems
monobactams
target: folic acid metabolism
sulphonamides
trimethoprim
target: DNA Gyrase
Quinolones
Target: DNA directed RNA polymerase
rifampicin
target: protein synthesis
30S
aminoglycosides
tetracyclines
target: protein synthesis
50S
macrolides
chloramphenicol
clindamycin
inhibit protein synthesis by binding at the P site at the ribosomal 50S subunit
Oxazolidinones
gram staining procedure
reagent:
crystal violet 1st stain (-) violet
gram iodine mordant (-) violet
95% etOH decolorizing agent
(-) colorless
saffranin counter stain
(-) red/pink
(+) violet/blue
peptidoglycan traps crystal violet
gram-positive bacteria
crystal violet is easily rinsed away revealing red dye
gram negative bacteria
a key bacterial enzyme involved in peptidoglycan synthesis, which is essential for bacterial cell wall integrity
-also known as a Penicillin-Binding Protein (PBP) because β-lactam antibiotics (like penicillins and cephalosporins) target it
Transpeptidase
refers to non-traditional or secondary pathways through which a drug exerts its effect
Alternative Theory
Umbrella Effect
Cell Wall Synthesis Inhibitors
- Penicillins
- Cephalosporins
- β-lactams
- Glycopeptides
- Carbapenems
- Cycloserine
- Bacitracin
β-lactam ring
4 membered ring
Resistance to Penicillins
- Physical Barrier
- Presence of β-lactamase enzymes
- High levels of transpeptidase enzyme produced
- Affinity of transpeptidase enzyme to penicillin
- Efflux process
- Mutations and genetic transfers
Resistance to Penicillins
* Physical Barrier
Some bacteria have an outer membrane that acts as a barrier, preventing penicillins from reaching their target (transpeptidase enzymes).
Example: Gram-negative bacteria (e.g., Pseudomonas aeruginosa)
Solution: Use β-lactams with porin penetration ability (e.g., carbapenems)
Resistance to Penicillins
* Presence of β-lactamase enzymes
⚠️ β-lactamases are bacterial enzymes that break down the β-lactam ring, rendering penicillin ineffective
Example: Penicillinase, ESBLs (Extended-Spectrum β-Lactamases), and Carbapenemases destroy β-lactam antibiotics.
Solution: Combine penicillins with β-lactamase inhibitors (e.g., amoxicillin + clavulanic acid).
Resistance to Penicillins
* High levels of transpeptidase enzyme produced
📈 If bacteria overproduce transpeptidase (PBP), there are more enzyme molecules for penicillins to bind, reducing their effectiveness
🔹 Example: Some Enterococcus species increase PBP production, leading to resistance.
🔹 Solution: Higher antibiotic doses or alternative drugs.
Resistance to Penicillins
* Affinity of transpeptidase enzyme to penicillin
🔄 Bacteria alter the binding site of transpeptidase (PBP), so penicillins can no longer attach effectively.
🔹 Example:
Methicillin-Resistant Staphylococcus aureus (MRSA) produces PBP2a (encoded by the mecA gene), which has a low affinity for β-lactams.
Streptococcus pneumoniae modifies PBPs to reduce β-lactam binding.
🔹 Solution: Use non-β-lactam antibiotics (e.g., vancomycin for MRSA).
Resistance to Penicillins
* Efflux process
🚛 Some bacteria use efflux pumps to actively pump out penicillins before they can act.
🔹 Example: Pseudomonas aeruginosa and Escherichia coli use RND efflux pumps to remove β-lactams.
🔹 Solution: Efflux pump inhibitors (though not widely available).
Resistance to Penicillins
* Mutations and genetic transfers
✔ Mutations – Spontaneous changes in bacterial DNA can lead to reduced drug binding or increased enzyme production.
✔ Horizontal Gene Transfer – Resistance genes spread via:
Conjugation (plasmids carrying β-lactamase genes)
Transformation (uptake of resistance genes from dead bacteria)
Transduction (bacteriophages transferring resistance genes)
🔹 Example: Neisseria gonorrhoeae acquires β-lactam resistance through genetic recombination.
🔹 Solution: Combination therapy and careful antibiotic stewardship.
are bacterial enzymes that hydrolyze (break down) the β-lactam ring of antibiotics, rendering them ineffective. These enzymes are one of the most common mechanisms of resistance to penicillins, cephalosporins, carbapenems, and monobactams.
β-Lactamase Enzymes
This reaction occurs in acidic environments, such as the stomach, and is a key reason why some penicillins have poor oral bioavailability.
Penicillins contain a β-lactam ring, which is highly reactive and susceptible to
Acid-Catalyzed Ring Opening
Influence of Acyl Side Chain on Stability of penicillin
The acyl side chain (R group) of penicillins plays a critical role in determining:
✅ Acid stability (for oral bioavailability)
✅ β-lactamase resistance (enzyme stability)
✅ Spectrum of activity
a secreted enzyme that hydrolyzes penicillin and other penicillinase-susceptible compounds into inactive penicilloic acid.
S. aureus- penicillinase producing
penicillinase
Penicillins
- Natural Penicillins
- Acid-resistant
- Penicillinase-resistant
- Broad-spectrum
- Aminopenicillins
- Carboxypenicillins
- Ureidopenicillins
Natural Penicillins
- Benzylpenicillin
- Pen G
Produced by fermentation
Corn steep liquor
Phenylacetic acid
Hydrolized by acid
Cannot be taken orally
- Pen G
- Phenoxymethylpenicillin
- Pen V
Phenoxyacetic acid
Stable in acid
Given orally
- Pen V
- Penicillin analogues
- Acid-resistant
- Phenoxymethylpenicillin
- Pen V
- Ampicillin
Acid resistant due to electron withdrawing group
Penicillin analogues
* Penicillinase-resistant
- Methicillin
- Nafcillin
- Temocillin
“Bulky = steric hindrance” = protect beta lactams
- Isoxazolyl Pen
- Oxacillin
- Cloxacillin = tx boils (S. Aureus)
- Flucloxacillin
- ampicillin – Co-fluampicil
- Dicloxacillin
Addition of halogen increases drug activity
Both bulky & acid resistant
prevent penicillinase from accessing the β-lactam ring.
primarily due to the bulky electron-withdrawing groups in their acyl side chains
Penicillin analogues
* Broad-spectrum
“Anti pseudomonal penicillin”
- Improved ability to cross cell membrane
- ↓ susceptibility to β-lactamase
- ↑ affinity to transpeptidase
- Approaches
- Hydrophobic group on side chain – ↑ activity against G+
- Hydrophilic group on side chain – ↑ activity against G-
- -NH2, -OH, -CO2H = penetrate (g-) cell membrane via porins
Penicillin analogues
* Broad-spectrum
* Aminopenicillins
- Ampicillin
- Amoxicillin
- Clavulanic acid – Co-amoxicillin
Penicillin analogues
* Broad-spectrum
* Carboxypenicillins
- Carbenicillin
- Carfecillin
- Ticarcillin
Penicillin analogues
* Broad-spectrum
* Ureidopenicillin
- Azlocillin
- Mezlocillin
- Piperacillin
- Tazobactam
Penicillin synergism
- Clavulanic acid
- Probenecid
Cephalosporium acremonium (Acremonium chrysogenum)
Cephalosporins
Cephalosporins
- First Gen
- Second Gen
- Third Gen
- Fourth Gen
- Fifth Gen
First Generation: Cephalosporins
- good activity against g(+) bacteria & relatively modest activity against g(-) microorganisms
Fa, Pha
Cefadroxil
Cefazolin
Cephalexin
Cephalothin
Cephapirin
Cephradine
Second Generation: Cephalosporins
- increased activity against g(-) microorganisms
➢Cefamandole, Cefuroxime, Cefonicid, Ceforanide, Cefaclor:
active against H. influenzae
➢Cefoxitin, Cefotetan, Cefmetazole:
active against B. fragilis
fu, fx, fo, fp
Cefaclor
Cefamandole
Cefonicid
Cefuroxime
Cefuroxime
axetil
Cefprozil
Loracarbef
Cefoxitin
Cefmetazole
Cefotetan
Ceforanide
Third Generation: Cephalosporins
- less active than 1st
-generation agents against g(+) cocci - much more active against the Enterobacteriaceae,
including β-lactamase-producing strains
➢ Ceftazidime, Cefoperazone: active against P. aeruginosa
➢ Ceftizoxime, Moxalactam: active against B. fragilis
*ft)
Cefoperazone
Cefotaxime
Ceftazidime
Ceftizoxime
Ceftriaxone
Cefixime
Cefpodoxime
proxetil
Cefdinir
Cefditoren
pivoxil
Ceftibuten
Moxalactam
Fourth Generation: Cephalosporins
- extended spectrum of activity compared with the 3rd generation
- increased stability from hydrolysis by plasmid & chromosomally mediated β-lactamases
fp
Cefepime
Cefpirome
1st gen
ceph except for cefadroxil & cefalosin
2nd gen
cef except for cefuroxime and lovacarbef
3rd gen
end in -one or -ime except cefdinir & cefditorn
4th gen
cefpirome & cefepime
β-Lactams Antibiotics
- Carbapenems
- Monobactams
- Intact B-lactam ring
- S atom
- Bicyclic ring system
- Carboxyl group
- Amide side chain
Carbapenems
- Thienamycin
- Streptomyces cattleya
- Imipenem
- Susceptible to hydrolysis by
dehydropeptidase enzyme
- Susceptible to hydrolysis by
- Meropenem
Monobactams
Aztreonam
* Chromobacterium violaceum
* Effective against Gentamicin resistant orgs
β-Lactamase Inhibitor
- Clavulanic acid
- Penicillanic acid sulfone derivatives
- Olivanic acids
Clavulanic acid
- Streptomyces clavuligerus
- Amoxicillin = Augmentin
- Ticarcillin = Timentin
Penicillanic acid sulfone derivatives
- Sulbactam
- Ampicillin = Unasyn
- Tazobactam
- Piperacillin = Tazocin / Zosyn
Olivanic acids
- MM 13902
- Streptomyces olivaceus
Cycloserine
- Streptomyces garyphalus
- Inh L-alanine racemase and D-ala-D-ala ligase
Bacitracin
- Bacillus subtilis
- Binds to lipid carrier of NAM and prevents transport across the cell membrane
Glycopeptides
- Vancomycin
- Streptomyces orientalis
- Teicoplanin
- Actinoplanes teichomyceticus
- Eremomycin
vancomycin
Active Against (Gram-Positive Bacteria Only)
A last-resort antibiotic for serious Gram-positive infections, especially MRSA and C. difficile colitis.
vancomycin
prevents N-acetylmuramic acid (NAM)- and N-acetylglucosamine (NAG)-peptide subunits from being incorporated into the peptidoglycan matrix, the major structural component of Gram-positive bacterial cell walls.
It binds specifically to the D-Ala-D-Ala terminal of the peptidoglycan precursors, forming hydrogen bonds.
This blocks transglycosylation and transpeptidation, preventing proper cell wall synthesis
Agents Acting on
Plasma Membrane
- Ionophores
- Polymixin B
- Killer nanotubes
- Cyclic lipopeptides
Ionophores
- Valinomycin
*Valinomycin - esters
*Valinomycin- amides - Gramicidin A
Polymixin B
- Bacillus polymyxa
Killer nanotubes
- Cyclic peptides that will self-assemble in the cell membranes of bacteria to form tubules
Cyclic lipopeptides
- Daptomycin
- Streptomyces roseosporus
Inhibitors of Cell Metabolism
- Sulfonamides
- Trimethoprim
- Sulfones
Sulphonamides (SN)
*are competitive antagonists and structural analogues of p-aminobenzoic acid (PABA), which is essential for folic acid synthesis in bacteria
*inhibit dihydropteroate synthetase, the enzyme responsible for folate production
This inhibition prevents the formation of:
✅ Dihydrofolate
✅ Tetrahydrofolate (THF)
✅ DNA synthesis
Sulfonamides
- Sulfa-drugs – Prontosil → Sulfanilamide
Sulfanilamide analogues
- Sulfathiazole
- Sulfadiazene
- Sulfadoxine
- pyrimethamine = Fansidar
Trimethoprim
- sulfamethoxazole = Cotrimoxazole
Protein Synthesis Inhibitor
- Aminoglycosides
- Tetracyclines
- Chloramphenicol
- Macrolides
- Lincosamides
- Streptogramins
- Oxazolidinones
Aminoglycosides
- Streptomycin
- Streptomyces griseus
- Gentamicin
Tetracyclines
- Chlortetracycline (Aureomycin)
- Streptomyces aureofaciens
- Tetracycline
- Doxycycline
Chloramphenicol
- Streptomyces venezuela
Macrolides
- Erythromycin
- Streptomyces arythreus
- Azithromycin
- Clarithromycin
Lincosamides
- Lincomycin
- Streptomyces lincolnensis
- Clindamycin
Streptogramins
- Pritinamycin
- Streptomyces pristinaespiralis
- Quinupristin
- Dalfopristin
Oxazolidinones
- Linezolid
targets ribosomes 30S
aminoglycosides
tetracycline
target ribosome 50s
Streptogramins
Tetracyclines Chloramphenicol
Clindamycin
Macrolides
Linezolid
(NA) Nucleic Acid Transcription and Replication
Inhibitors
- Quinolones and fluoroquinolones
- Aminoacridines
- Rifamycins
- Nitroimidazoles and Nitrofurantoin
- Miscellaneous agents
Quinolones and Fluoroquinolones
- Nalidixic acid
- Enoxacin
- Ciprofloxacin
- Ofloxacin
- Levofloxacin
- Moxifloxacin
Aminoacridines
- Proflavine
Rifamycins
- Rifampicin
- Rifamycin B
- Streptomyces mediterranei
Naphthalene ring (2 6 memebered ring)
Nitroimidazoles and Nitrofurantoin
- Metronidazole
Doc for GAT
No2 -> free radical-> electrophile
= interpolate with DNA - Nitrofurantoin
UTI
No2 -> free radical-> electrophile
= interpolate with DNA
Miscellaneous agents
- Methenamine
- Fusidic acid
- Fusidium coccineum
- Isoniazid - hepatotoxic
Act by catalaze peroxidase enzyme
Inhibit many pathways to synthesize micolic acid - Ethambutol- can cause optic neuritis, peripheral neuropathy
Give vit B
- Pyrazinamide- pro drug
Act into pyrazinoic acid (poa)
Metabolized to formaldehyde
beta lactam moa
inhibit bacteria cell wall biosynthesis
aminoglycoside moa
inhibit the synthesis of proteins by bacteria leading to cell death
glycopeptides moa
inhibit bacteria cell wall biosynthesis
ansamycin moa
inhibit the synthesis of RNA by bacteria leading to cell death
streptogramins moa
inhibit the synthesis of proteins by bacteria leading to cell death
quinolone moa
interfere with bacterial DNA replication and transcription
lipopetide moa
disrupt multiple cell membrane functions leading to cell death
chloramphenicol moa
inhibits synthesis of proteins preventing growth
sulfonamides moa
prevent bacteria growth and multiplication
tetracycline moa
inhibit protein synthesis preventing growth
macrolide moa
inhibit protein synthesis, occasionally leading to cell death (high dose)
Gram staining
95% etOH replacement
Acetone
Denatured alcohol
Penicillin structure
Beta lactam ring
Bicyclic syatem
Aminoacyl side chain
COOH or COO- (carboxylate)
