ANTIBACTERIAL AND ANTIFUNGAL AGENTS

Question 1

DNA localisation

Answer 1

Bacteria are ‘prokaryotes’ ie their DNA exists as a ring-like structure in the cytoplasm
Fungi are ‘eukaryotes’ ie their DNA is separated from the cytoplasm by a nuclear membrane

Question 2

Size

Answer 2

Bacterial cells are much smaller than fungal cells

Question 3

Structure

Answer 3

Bacterial cells are uniform simple structures

Fungal cells may have a complex structure and the same organism may have many different forms (hyphae, spores etc)

Question 4

Cellular processes

Answer 4

Fungal protein and DNA synthesis very similar to human processes

Question 5

Antibiotics

Answer 5

Chemical products of microbes that inhibit or kill other organisms

Question 6

Antimicrobial agents (antibacterial, antifungal, antiviral);

Answer 6

Antibiotics, Synthetic compounds with similar effect
Semi-synthetic i.e. modified from antibiotics: Different antimicrobial activity/spectrum, pharmacological properties or toxicity. Terms antibiotic and antibacterial agent are often used interchangeably

Question 7

Bacteriostatic/ fungistatic

Answer 7

Inhibit growth e.g. protein synthesis inhibitors

Question 8

Bacteriocidal/ fungicidal

Answer 8

Kill E.g. cell wall-active agents

Question 9

Minimum Inhibitory Concentration

Answer 9

MIC Minimum conc. of antimicrobial agent at which visible growth is inhibited

Question 10

Minimum bactericidal/fungicidal concentration

Answer 10

MBC/MFC: Minimum concentration of antimicrobial agent at which most organisms are killed.

Question 11

Synergism

Answer 11

Activity of two antimicrobials given together is greater than the sum of their activity if given separately

Question 12

Antagonism

Answer 12

One agent diminishes the activity of another

Question 13

Indifference

Answer 13

Activity unaffected by the addition of another agent

Question 14

Bacterial cell wall

Answer 14

Peptidoglycan:
Major component of bacterial cell wall
Both Gram-positive and Gram-negative
Polymer of glucose-derivatives, N-acetyl muramic acid (NAM) and N-acetyl glucosamine (NAG)
No cell wall in animal cells so Ideal potential for selective toxicity

Question 15

Cell wall synthesis inhibitors

• Antibacterial agents (classes)

Answer 15

– β-lactams

– Glycopeptides

Question 16

Fungal cell wall

Answer 16

β-1,3-glucan:
Large polymer of UDP-glucose
50 60% of the dry weight of the fungal cell wall
Form a fibrous network on the inner surface of the cell wall. Synthesized by β-1,3-glucan synthase
No cell wall in animal cells so Ideal potential for selective toxicity

Question 17

Cell wall synthesis inhibitors

• Antifungal agents

Answer 17

– Echinocandins

Question 18

Beta-lactams (antibacterial: huge class of antibiotic)

Answer 18

First true antibiotics in clinical practice = Benzylpenicillin. All contain β-lactam ring. Four-membered ring structure (C-C-C-N). Structural analogue of D-alanyl-D-alanine. Interfere with function of ‘penicillin binding proteins’ which are trans-peptidases enzymes involved in the peptidoglycan cross-linking.

Question 19

PENICILLINS

Answer 19

Benzylpenicillin, phenoxymethylpenicillin, flucloxacillin relatively narrow spectrum
Broad spectrum penicillin’s: amoxicillin (now narrower) and pivmecillinam. Penicillinase-resistant penicillin: flucloxacillin. IF SOMETHING ENDS IN CILLIN: IT IS A BETA LACTAM.

Question 20

CEPHALOSPORIN’S:

Answer 20

cephalexin, cefuroxime, cefotaxime, ceftriaxone, ceftazidime broad spectrum and arranged into generations.

Question 21

CARBAPENEMS

Answer 21

Ertapenem, imipenem, meropenem  Extremely broad spectrum

Question 22

MONOBACTAM

Answer 22

Aztreonam  gram negative activity only. Has only one ring so not got same allergic implications

Question 23

-lactamase enzymes

Answer 23

are enzymes that hydrolyse (inactivate) β-lactams. It is a common mechanism of resistance to β-lactam antibiotics. Different β-lactamase enzymes confer resistance to a narrow or wide range of β-lactams eg:
– Staphylococcal β-lactamase – some penicillins only
– ‘Extended spectrum β-lactamase’ (ESBL) – penicillins and cephalosporins
– Carbapenemases (eg NDM1) – carbapenems

Question 24

β-lactam/β-lactamase inhibitor combinations (BLBLI)

Answer 24

• Amocixillin-clavulanate (Augmentin): Increases the spectrum of amoxicillin
• Piperacillin-tazobactam (Tazocin: Increases the spectrum of piperacillin
• ESBL and carbapenemase BLBLIs: Work in progress
Problems with BLBLIs: Very broad spectrum, so predispose to C. difficile infection. Names do not end with –illin or start with cef-. Importance of penicillin allergy may be missed

Question 25

AMINOGLYCOSIDES: gentamicin and amikacin: Protein synthesis inhibitors

Answer 25

Bind to 30S ribosomal subunit. Mechanism of action not fully understood

Question 26

Macrolides, Lincosamides and Strepogramins (MLS): Protein synthesis inhibitors

Answer 26

Erythromycin, clarithromycin (macrolides). Clindamycin (lincosamide) bind to 50S ribosomal subunit. Inhibit protein elongation. Azithromycin also.

Question 27

Glycopeptides: (antibacterial) Vancomycin and Teicoplanin

Answer 27

Large molecules, bind directly to terminal D-alanyl-D-alanine on NAM pentapeptides. Inhibit binding of trans peptidases and peptideoglycan cross-linking. Gram +ve activity: Can’t penetrate Gram –ve outer membrane porins

Question 28

Quinolones & fluroquinolones: ciprofloxacin and levofloxacin DNA synthesis inhibitors

Answer 28

Inhibit one or more of two related bacterial enzymes. DNA gyrase and topoisomerase IV. Involved in remodelling of DNA during DNA replication. Examples Nalidixic acid1, ciprofloxacin2, levofloxacin2. Quinolones are effective against bacteria only.

Question 29

Tetracyclines: doxycycline: Protein synthesis inhibitors

Answer 29

Bind to 30S ribosomal subunit. Inhibit translation by interfering with binding of tRNA to rRNA. Tigecycline is a modern derivative of tetracyclines with a similar mechanism of action and a much broader spectrum. Lymocylin part of this and used for acne.

Question 30

rimethoprim and sulphonamides: DNA synthesis inhibitor

Answer 30

Both agents inhibit folate synthesis.

Trimethoprim - dihydrofolate reductase. Sulfonamides - dihydropteroate synthetase

Question 31

Trimethoprim and co-trimoxazole

Answer 31

Commonly used to treat UTI. Co-trrimoxazole is effective against pneumocystic which is a fungus.

Question 32

• Linezoid: Protein synthesis inhibitors  Oxazolidinones

Answer 32

Inhibits initiation of protein synthesis and binds 50S ribosomal subunit. Inhibits assembly of initiation complex. May also bind to 70S subuniy. Other antibacterial protein synthesis inhibitors: Mupirocin and fusidic acid.

Question 33

ANTIFUNGALS

Protein synthesis in fungi

Answer 33

Fungi are eukaryotes so share the same mechanisms of protein synthesis with humans
Probably for this reason protein synthesis is not a target for antifungal agents

Question 34

DNA synthesis in fungi

Answer 34

5 fluorocytosine (5FC) is a fungal DNA inhibitor, developed as a putative anti-cancer drug
Selectively taken into fungal cells by a fungal enzyme (cytosine permease). Selective toxicity poor. Not used often.

Question 35

Cell membrane agents

Answer 35

• Azoles e.g. lotrimazole and fluconazole
• Terbinafine Inhibit synthesis of ergosterol A component of fungal cell membranes But not human or bacterial cells.
• Amphotericin B (and nystatin) Bind to ergosterol causing physical damage to the membrane

Question 36

Echinocandins: anidulafungin

Answer 36

Mode of action: Inhibition of β-1,3-glucan synthase. Construction of severely abnormal cell wall
Examples: Anidulafungin, Caspofungin and Micafungin.