Antibacterial & Antifungal Agents Flashcards
Antimicrobials inhibit critical process in bacterial/fungal cells.
These processes include:
Enzymes, molecules or physical structures
- cell wall
- protein synthesis
- DNA synthesis
- RNA synthesis
- membrane function
Definition of antibiotics?
Chemical products of microbes that inhibit or kill other organisms
What are antimicrobial agents?
(antibacterial, antifungal, antiviral)
- Antibiotics
- Synthetic compounds with similar effect
- Semi-synthetic i.e. modified from antibiotics
Different antimicrobial activity/spectrum, pharmacological properties or toxicity
What is selective toxicity?
Inhibit critical process in bacterial/fungal cells with minimal harm to the patient
Define bacteriostatic/fungistatic
Capable of inhibiting the GROWTH or reproduction of bacteria.
Mainly protein synthesis inhibitors
Define bacteriocidal/fungicidal
Causes cell death (kill organism outright)
Mainly cell wall-active agents
How do bacteriostatic/fungistatic antimicrobials typically work?
Mainly protein synthesis inhibitors
How does bacteriostatic differ from bacteriocidal?
Bacteriostatic: Capable of inhibiting the growth or reproduction of bacteria. Different from bactericidal (capable of killing bacteria outright).
Define minimum inhibitory concentration (MIC)
The minimum concentration of an antimicrobial agent at which VISIBLE GROWTH is inhibited
i.e. lower MIC = organism more sensitive to antimicrobial
Define minimum bactericidal/fungicidal concentration (MBC/MFC)
The minimum concentration of antimicrobial agent at which most organisms ARE KILLED
Define synergy
When the effect of a COMBINATION of two antimicrobial agents is GREATER THAN the sum of the effects observed with the two drugs INDEPENDENTLY
Define antagonism
Activity of two antimicrobials given together is LESS THAN the activity of either if given separately
Define the antimicrobial spectrum
Range of bacterial/fungal species likely to be sensitive to a particular antibacterial/antifungal agent
What is a broad spectrum antibiotic?
Kills MOST TYPES of bacteria/fungi encountered
What is a narrow spectrum antibiotic?
Kills only a NARROW RANGE of organisms
Which spectrum of antibiotic should be used?
The narrowest spectrum antibiotic that is appropriate should be used at all times
(want to upset normal flora as little as possible)
How does the spectrum of organisms covered by an antimicrobial agent change during its clinical lifespan?
Tends to become narrower as resistance develops in the target microbial population
E.g. Penicillin was once a broad spectrum antibiotic, but now it is considered to be “narrow spectrum”.
One of the major groups of antimicrobial agents are CELL WALL SYNTHESIS INHIBITORS
What is the major structural component of bacterial cell wall?
Peptidoglycan
Why are cell wall synthesis inhibitors ideal?
- Cell wall required for survival of bacteria
2. no cell wall in animal cells –> ideal potential for selective toxicity
What is peptidoglycan?
Polymer of glucose-derivatives, N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
Oligopeptide crosslinks formed by transpeptidases known as “penicillin binding proteins” (PBPs).
What are penicillin-binding proteins?
A group of proteins that are characterised by their affinity for and binding of penicillin. They are a normal constituent of many bacteria; the name just reflects the way by which the protein was discovered.
PBPs are members of a subgroup of enzymes called transpeptidases.
Involved in the synthesis and maintenance of peptidoglycan
What are the 2 main cell wall synthesis inhibitors among the antibacterial agents?
- β-lactams (beta-lactams, penicillins)
2. Glycopeptides
Describe structure and action of β-lactam antibiotics
All b-lactam antibiotics have a four-membered ring structure - the b-lactam ring
They act by inhibiting penicillin binding proteins: enzymes involved in the synthesis and maintenance of peptidoglycan.
What are the 4 major groups of β-lactam antibiotics?
- Penicillins
- Cephalosporins
- Carbapenems
- Monobactams
Give examples of penicillins
What spectrum?
Benzylpenicillin, amoxicillin, flucloxacillin
Relatively narrow spectrum§
Give examples of Cephalosporins
What spectrum?
Cefuroxime, ceftazidime etc.
Broad spectrum - Arranged into ‘generations’
Give examples of Carbapenems
What spectrum?
Meropenem, imipenem
Extremely broad spectrum
Give examples of Monobactams
What spectrum?
Aztreonam
Gram-negative activity only and has slightly different ring structure
Contraindications of β-lactam antibiotics?
the risk of cross-reactivity -contraindication of all β-lactam antibiotics in patients with a history of: severe allergic reactions (urticaria, anaphylaxis, interstitial nephritis) to any β-lactam antibiotic.
N.B. patients with penicillin allergy can usually be given Aztreonam (different structure)
What are the 2 main examples of glycopeptides (cell wall synthesis inhibitor)?
Vancomycin, teicoplanin
Mechanism of glycopeptides?
Large molecules, bind to terminal amino acids on NAM pentapeptides
Inhibit binding of transpeptidases and thus peptidoglycan cross-linking
What organisms are glycopeptides effective against?
Gram-positive –> unable to penetrate Gram-negative outer membrane
What are the 5 basic mechanisms of antibiotic action against bacterial cells?
- Inhibition of Cell Wall Synthesis (most common mechanism)
- Inhibition of Protein Synthesis (Translation) (second largest class)
- Alteration of Cell Membranes.
- Inhibition of Nucleic Acid Synthesis.
- Antimetabolite Activity.
Where does protein synthesis take place in bacteria?
Protein synthesis takes place on the bacterial ribosome
RNA moves through the ribosome and is translated into a polypeptide chain
What are bacterial ribosomes composed of? How does this differ to eukaryotic cells?
50S (large) and 30S (small) subunits combine to form 70S initiation complex
60S and 40S in eukaryotic cell
What does the S in 50S refer to?
S=Svedberg units; relative sedimentation rate
What are the 6 main types of bacterial protein synthesis inhibitors?
- Aminoglycosides (e.g. gentamicin, amikacin)
- Macrolides (e.g. erythromycin, clarithromycin) and lincosamides (clindamycin)
- Tetracycline, doxycycline
- Linezolid
- Mupirocin
- Fusidic acid (not used very much)
What are Tigecycline and eravacycline?
Synthetic derivatives of tetracyclines with a similar mechanism of action and a much broader spectrum
What does Linezolid target?
Gram-positive infections
What is Mupirocin used for?
Topical agent for staphylococcal/streptococcal infection
How do antibiotics that inhibit DNA synthesis work?
Inhibit folate synthesis –> Folic acid is a precursor of purine synthesis
What 2 drugs inhibit folate synthesis in order to inhibit DNA synthesis?
- Trimethoprim - dihydrofolate reductase
2. Sulfonamides
What is Trimethoprim commonly used to treat?
UTIs
DNA synthesis pathway in bacteria:
- Bacterial para-amino benzoic acid (PABA)
- Dihydropteroate
- Dihydrofolate
(dietary folate) - Tetrahydrofolate (folinic acid)
- Thymidine/purine synthesis
- DNA
Which point of this pathway does:
a) sulfonamides target?
b) trimethoprim target?
a) The step from PABA –> dihydropteroate by inhibiting Dihydropteroate synthetase
b) The step from Dihydrofolate (dietary folate) –> Tetrahydrofolate (folinic acid) by inhibiting Dihydrofolate reductase
What enzyme does sulfonamides inhibit?
Dihydropteroate synthetase
What enzyme does trimethoprim inhibit?
Dihydrofolate reductase
What is Co-trimoxazole a combination of?
What is it used to treat?
trimethoprim-sulfamethoxazole
- Has antibacterial effects
- Has antifungal effects specific to Pneumocystis jiroweci
- Has antiparasitic effects specific to Toxoplasma gondii
What are the antifungal effects of Co-trimoxazole specific to?
Pneumocystis jiroweci
What are the antiparasitic effects of Co-trimoxazole specific to?
Toxoplasma gondii (toxoplasmosis)
What is the action of fluoroquinolones? Mechanism?
DNA synthesis inhibitors:
- Inhibit one or more of two related bacterial enzymes: DNA gyrase and topoisomerase IV
- Involved in remodelling of DNA during DNA replication
What are 2 examples of fluoroquinolones?
Ciprofloxacin, levofloxacin
How do RNA synthesis inhibitors work?
- RNA polymerase inhibitor
- Prevents synthesis of mRNA
Whats an example of an antibiotic that acts as an RNA synthesis inhibitor?
Rifampicin
What is Rifampicin primarily used in the treatment of?
anti-tuberculous chemotherapy
Why is Rifampicin ALWAYS used in combination with other antimicrobial agents?
Easy for organisms to develop mutations in their RNA polymerase which render them resistant to Rifampicin
Some antibiotics target the cell membrane. What are some examples of these?
- Colistin/polymyxin E (Gram-negatives)
- Daptomycin (Gram-positives)
Mechanism of Daptomycin?
Is a cyclic lipopeptide that causes destruction of outer membrane or cytoplasmic membrane of Gram-positive agents
Summary of antibacterial mechanisms:
- Cell wall synthesis
- Glycopeptides
- Beta-lactams - penicillins and cephalosporins - Protein synthesis:
- Macrolides/lincosamides
- Aminoglycosides
- Tetracyclines
- Linezolid Etc. - DNA synthesis
- Trimethoprim/ sulfonamides
- Quinolones
- (Metronidazole) - RNA synthesis:
- Rifampicin - Cytoplasmic membrane
- Daptomycin - Outer membrane
- Colistin (polymyxins)
What are pathogenic fungi divided into?
- Filamentous fungi (moulds)
2. Yeasts
What are dimorphic fungi?
Fungi that can exist in the form of both mould and yeast.
This is usually brought about by change in temperature.
What parts of the fungal cell do antifungals target?
- Cell wall
- Cell membrane
- DNA synthesis
- Protein synthesis
What sterol is found in cell membranes of fungi and protozoa?
Ergosterol
Serves many of the same functions that cholesterol serves in animal cells.
Why is selective toxicity for antifungals limited?
DNA and protein synthesis in animal cells is relatively similar to in fungal cells
What is the fungal cell wall composed of?
β-1,3-glucan (synthesized by β-1,3-glucan synthase)
Why is the fungal cell wall an excellent target for antifungal therapy?
As the components of the fungal cell wall are not present in humans
i.e. animal cells have no cell wall
Main example of antifungal cell wall inhibitor?
Echinocandins (antifungal)
- Anidulafungin
- Caspofungin
- Micafungin
Mechanism of Echinocandins?
- Enzyme inhibitors
- Inhibit β-1,3-glucan synthase
Why do Echinocandins have relatively few side effects?
Their target is specific to fungi
What are the 3 groups of antifungals that target the cell membrane (i.e. target Ergosterol)?
- Azoles (clotrimazole, fluconazole, voriconazole)
- Terbinafine
- Amphotericin B (and nystatin)
Mechanism of Terbinafine?
Inhibit synthesis of ergosterol (a component of fungal cell membranes but not human or bacterial cells)
Mechanism of Amphotericin B (and nystatin)?
Bind to ergosterol causing physical damage to the membrane
What is the only antifungal agent to inhibit RNA/DNA synthesis?
5-fluorocytosine
Mechanism of 5-fluorocytosine?
Transported into fungal cells by a fungal enzyme (Cytosine permease)
Metabolised into inhibitory molecules (mainly 5-fluorouracil)
What is 5-fluorocytosine used to treat?
Use largely historic but still used to treat cryptococcal meningitis
Summary of antifungal mechanisms
- RNA/DNA synthesis
- 5-fluorocytosine (5FC) - Cell membrane synthesis (ergosterol)
- Azoles
- Terbinafine - Cell membrane integrity
- Amphotericin B - Cell wall synthesis
- Echinocandins
Empiric vs targeted therapy?
Empiric Therapy. choosing antibiotic therapy with a clinical educated guess.
Targeted Antibiotic Therapy. Choosing therapy based on a definitive organism
As your level of knowledge of infecting organisms increases, the antimicrobial spectrum of agents used should decrease
