General properties of antimicrobial agents Flashcards
What is meant by selective toxicity?
Drugs that disrupts microbial functions not found in the eukaryotic cells.
Leads to:
- Greater selectivity
- Greater therapeutic range
What are the classes of the antimicrobial agents?
1) cell wall synthesis inhibitors
2) Disruptors of cell wall/membrane
3) Protein synthesis inhibitors
4) Metabolic at antagonists
5) Nucleic acid synthesis/manipulation inhibitors
State agents of cell wall synthesis inhibition
- Bacitracin
- beta-lactam
- Fosfomycin
- Glycopeptides
which agents affect the Structure and function of the cell membrane
- Colistin
- Daptomycin
- Polymyxin B
list agents that are Metabolic antagonists (Folic Acid synthesis)
- Trimethoprim
- Sulfonamides
What agents are nucleic acid (DNA) inhibitors?
- Quinolones
- Nitrofurantoin
- Nitroimidazole
Protein synthesis inhibition agents
- Aminoglycosides
- Lincosamide
- Macrolides
- Tetracyclines
G+ve cell wall structure and stain
- Cytoplasmic membrane
- Rigid, thick, cross-linked peptidoglycan
- Purple stain
G-ve cell wall structure and stain
- Cytoplasmic membrane
- Thin, cross-linked peptidoglycan
- Outer membrane
- pink stain
What gives cell wall rigidity and what is it composed of?
-Peptidoglycan gives cell wall it rigidity
-Peptidoglycan is made of repeating sugars that are crossed linked:
+ N-acetyl glucosamine (NAG)
+ N-acetyl muramic acid (NAM)
- has peptide chain
What is the family of enzymes used to connect the sugar molecule peptide chain?
-Penicillin binding protein
or
-Transpeptidase
these are used interchangeably
How does PBPs work?
- reactive serin residue in the PBP with the penultimate D-alanine on the peptide chain.
- This remove the last reside (after the D-alanine).
- The PBP grabs another pentaglycine chain for another peptidoglycan chain and join them together.
How does Beta-lactam work
- It inhibits PBP.
- B-Lactam ring resembles D-alanyl-D-alanine section of peptide side chain.
- PBP bind irreversibly to lactam and not side chain
- No cross-linking leads to bactericidal lysis.
Why is the lactam made of?
Made of Lactone and amide
- Lactone is a cyclic carboxylic ester
what makes Beta lactam ring so reactive?
Made of 4 rings and so is strained
What are the types of B-lactam resistance?
- Intrinsic resistance
- Acquired resistance
what is intrinsic resistance?
Change in the structure or function of bacteria species.
eg no typical crosslinking
What is acquired resistance?
A previously sensitive bacterium acquires a mutation or new genetic material allowing it to resist activity of the agent
What is the mechanism of Beta-lactamase?
Lyses the 4 atom lactam ring. This reduces the strain and make it significantly less reactive.
What are the subgroups of penicillin?
- Natural penicillin
- Anti-staphylococcal penicillin
- Aminopenicillin
- Extended spectrum penicillin
Types of Natural penicillin
Penicillin V- oral
Penicillin G- injection (IM or IV)
Properties of natural penicillin
-Relatively hydrophobic side chain
-Majority of bacteria either intrinsically resistant or
have acquired resistance
-Susceptible to many β-lactamases
Examples of Anti-staphylococcal penicillin
Flucloxacillin Methicillin Cloxacillin dicloxacillin oxacillin
Properties of Anti-staphylococcal penicillin
-Bulky side chains: reduced binding by staphylococcal lactamases
- MRSA / MRSE have different PBPs (mecA gene / PBP2)
- Bulky, relatively hydrophobic side chains prevent
penetration through porins (v poor G- action)
P.S MRSA=Methicillin-resistant Staphylococcus aureus
Examples of Aminopenicillins
Amoxicillin
Ampicillin
Properties of Aminopenicillin
-Additional amino group on side chains increases hydrophilicity
• Pass better through porins
• Extends spectrum of G– activity
Examples of extended-spectrum penicillin
piperacillin
ticarcillin
Properties of Extended-spectrum penicillin
– Side chains enhance porin penetration
– More resistant to G- lactamases
– Often less active against G+ organisms
What is penicillin augmentation
and give some examples
-Penicillin and beta-lactamase inhibitor is given in combination
-amoxicillin-clavulanate (augmentin)
piperacillin-tazobactam (tazocin)
additional lactams as “decoy” substrate
properties of B-lactamase inhibitors
- Reactive molecule with high tendency to bind to βlactamases
- Thus, active antibiotic doesn’t get cleaved
- Increased activity against G+ / G- / anaerobes
Draw and describe the structure of cephalosporins.
- It has the nucleus and 2 main side chain
What are the 2 side chain modifications on cephalosporins representative of.
- R1: Antimicrobial activity including changed in water solubility and PBP affinity
- R2: Pharmacokinetic properties
What is the name of the 1st, 2nd, 3rd , 4th and 5th gen cephalosporins.
1st: Cefalexin
2nd: Cefuroxime
3rd: Ceftazidime, ceftraixone
4th: Cefepime,
5th: Ceftaroline
Feature of first generation cephalosporins.
Features of the side chain.
Good for: activity against G+ cocci
R1: Protection from staphylococcal b-lactamases NOT G-VE
No R2
2nd gen cephalosporins features and R side chain features
-More activity G-ve than 1st gen.
-less activity against G+ve
-R1: increased polarity, better porin entry
R2: minimal but quite polar
3rd gen features and R side chain features
- ceftriaxone, ceftazidime
- R1 Polar: Increased porin penetration
- Increased affinity for some PBPs
- Increased stability vs. G- b-lactamases
- ceftazidime active against Pseudomonas
- R2 - ceftriaxone has a long t1/2
4th and 5th gen cephalosporin features
*cefepime (4th)
aminothiazolyl group on R1 and polar pyrolidine group on R2
Pseudomonas
*ceftaroline (5th)
good activity against G+, including MRSA (PBP2a)
What are the names of Carbapenems class drugs
- Imipenem
- meropenem
- ertapenem
What spectrum of antimicrobials does the carbapenems cover
It is a very broad spectrum antibiotic
- G-VE G+ve and anaerobic
Name of a monobactam drug
-Aztreonam
What range of bacterial classes do monobactams work against
Aerobic G-ve so it it a narrow spectrum
feature of Monobactams
- Lone b-lactam ring
- Totally synthetic
- Combines advantageous properties from 3G cephalosporins
- Very low likelihood of reaction in penicillin-allergic patients (but R1 chain is very like ceftazidime)
Name 2 of the glycopeptides
Vancomycin
Teicoplanin
what are the origins of glycopeptides
From streptomyces organisms
MOA of glycopeptides
Inhibit cell wall synthesis by forming complex with substrate that make D-ala-D-ala
“slowly/weakly” bactericidal
By binding to the D-Ala-D-Ala terminal of the growing peptide chain during cell wall synthesis, resulting in inhibition of the transpeptidase
Glycopeptide spectrum
-Narrow spectrum
G+ve only as it is too large to enter into the porins of G-ve cells
Origin of Fosfomycin
Streptomyces organisms
What is the spectrum of Fofomycin
Broad-spectrum against G+ and G-
What is the MOA of Fosfomycin
- Inactivates MurA (inhibits peptidogylcan synthesis)
- Fosfomycin resistance enzymes are in existence on chromosome and transferrable plasmids
- FosA / FosB / FosX
- weakly bactericidal
Bacitracin origin
Bacillus subtilis organism
MOA of Bacitracin
Interferes with peptidoglycan synthesis
What is the spectrum of Bacitracin
Narrow-spectrum, usually for G+ organisms that cause skin infections
Name the antibiotic that disrupt the cell wall envelope
- Daptomycin
- Colistin
MOA of Daptomycin
enters into G-ve cell membrane, aggregates and causes leakage of ions
Bactericidal
MOA of Colistin
Attaches to lipopolysaccharide and phospholipid in G-ve cell membrane. Cause leaking of ions form within and major cell function
Bactericidal
which part of the prokaryote do most anti microbials bind to?
Most bind to the ribosomes of the prokaryote. Includes both the 30S and 50S
What are the different way a protein synthesis inhibitor can work?
They inhibit:
- Aminoacyl-tRNA binding
- Peptide bond formation
- mRNA reading
- Translocation
Features of Aminoglycosides
-2+ amino sugars and an aminocyclitol (C6) ring
Broad spectrum: aerobic G- rod and -certain G+
MOA of Aminoglycosides
- Binds to 30s ribosomal subunit (interferes with translation proofreading)
- Misreading of mRNA occurs
- False proteins produced
- Bactericidal
- unusual for protein inhibitors
What is the name of a common aminoglycosides
Streptomycin
gentamicin
what are some features of Macrolides
- contains 12 to 22 carbon lactone rings linked to one or more sugars
List some drugs that are macrolides
- Erythromycin
- Azithromycin
- Clarithromycin
Features and MOA of erythromycin
Moderate spectrum
Bacterial statin
Binds to 23S rRNA of 50S ribosome subunit and inhibits protein chain elongation
Features of azithromycin and clarithromycin
Broader spectrum and often time is more active that erythromycin
Structure and spectrum of Tetracycline:
4 ring with a variety of side chains
Moderately broad spectrum (most are at G+ than G-)
Bacteriostatic
MOA of tetracyclines
- Combine with 30S ribosomal subunit.
- inhibits binding of aminoacyl-tRNA molecules to the A site of the ribosomes
Tetracycline examples
Tetracycline
Doxycycline
Minocycline
Tigecycline
what are tetracycline, minocycline, doxycycline used for?
Treat ATYPICAL organisms: pneumonia, chlamydia, Lyme disease, Acne
Feature of tigecycline
It is a new variant
broad spectrum and given by IV
Chloramphenicol structure and spectrum
Nitrobenzene structure
Broad spectrum
Bacteriostatic
MOA of Chloramphenicol
Binds to 23S of 50S on ribosome.
Inhibits peptidyl transferase action
What is chloramphenicol used to to treat.
Typhoid fever
brain abscesses,
rickettsial and
chlamydial infections
Name some other protein synthesis inhibitors
Lincosamide
Oxazolidinone
Lincosamides (clindamycin)
principally G+ and anaerobes,
often reserved for relatively “difficult”, possibly multiorganism infections.
Adverse reactions; notorious for C. diff (“unique”)
oxazolidinone
synthetic antimicrobial that blocks the interaction of mRNA and ribosome
used to treat methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE)
List antibiotic agents that are metabolic antagonists.
- Trimethoprim
- Sulfamethoxazole
MOA of metabolic antagonist
effects the synthetic of nucleotides especially tetrahydrofolate, which is used for many things.
how does Sulfamethoxazole-trimethoprim combination work
Sulfamethoxazole has similar structure to para amino benzoic acid
Trimethoprim mimics dihydrofolate
synergistically inhibit synthesis of Tetrahydrofolate.
What is trimethoprim-sulfamethoxazole used to treat?
Very serious infections such as pneumonia or Nocardia infection
This is due to it being toxic: skin reaction and bone marrow
what ways can the resistance of sulfonamides occur in bacteria.
- Alteration of target enzyme
- Changes in permeability
- Hyperproduction of PABA may overcome blockade
Name some nucleic acid inhibitors
- Quinolones
- Metronidazole
Describe the structure of quinolones
It is a synthetic drug made with dual 4-quinolone rings
Spectrum of quinolones
Broad spectrum
MOA of quinolones
Act by inhibiting topoisomerases
- DNA gyrase
- Topoisomerase IV
List some drugs under the class of quinolones
- Nalidixic acid
- Ciprofloxacin
- Moxifloxacin
How does the resistance of bacteria to quinolones occur?
- Mutation in topoisomerase-encoding genes
- Porins-poor outer membrane
- Efflux pumps
MOA of metronidazole
The nitro group on the core ring must be reduced so that the drugs is active.
Only achieved in anaerobes
Free radicals are generated with case DNA damage and cell death
How does antimicrobial resistance occur
A random mutation that is selected
Where does resistance usually originate from
From the recipients normal flora and when present can be bred due selection pressure.`
Mechanism of Drug resistance
- Prevent entrance of drug
- drug can’t bind to or penetrate pathogen
- bacterial decrease in permeability
-Pump drug out- efflux pumps
- Inactivation of drug
- chemical modification of drug by pathogen
- Alteration of target enzyme or organelle
- Use of alternative pathways or increased production of target metabolite
what are the 6 potential b-lactam resistance
1) Peptidoglycan
Some organisms do not use peptidoglycan
2) Penetration into infected cells
b-lactams penetrate poorly into host cells
(ineffective against intracellular pathogens)
3) Porins in G-ve bacteria: reduce porins
Needed to gain access to PBPs. “Porin-poor” strains exist
4) Pumps
Efflux pumps transport antibiotics back out of the cell (most effective for G –ve as they can pump out of the outer membrane)
5) PBPs
Low affinity binding (may be acquired or intrinsic - vary between organisms anyway)(“acquired” includes MRSA, among others)
6) Penicillinases (b-lactamases)Enzymes that degrade b-lactam ring; descended from PBPs. Again many variations
How is resistance transmitted
-Chromosomal genes
*Passed on during cell division to “all” progeny
-Mobile genetic elements (plasmids, transposons, integrons) Genes on these can move within and / or be freely exchanged between bacteria
-Gene cassettes
“sets” of related or unrelated resistance genes can exist as separate genetic elements or can be part of transposon, integron or chromosome
How can the emergence of resistance be delayed.
1- Use drugs only when necessary
2- Achieve adequate concentration
3- use 2 or more drugs at the same time sometimes
4- develop new drugs, vaccination, use bacteriophages to treat bacterial disease.
List the Classes of antibiotics available?
Penicillin Cephalosporins Macrolides Carbapenems Aminoglycoside Glycoproteins Sulfonamindes Nitrofurans Licosamides Tetracycline Nitroimidazoles FLUOROQUINOLONES
