L19 Flashcards
1
Q
Antimicrobial agents
A
Agents that kill or inhibit growth of microbes
Physical or chemical - have no or low selectivity
2
Q
Chemical antimicrobial agents
A
- chemotherapeutic agents = antimicrobial drugs or antimicrobials, including:
- antibiotics = microbial products or derivatives e.g. penicillin
- synthetic antimicrobials e.g. sulphonamides
3
Q
The modern era began with the work of German physician Paul Ehrlich. What did he do
A
- Dyes can bind to microbial cells
- 1910: magic bullet- arsenic based salvarsan to treat SYPHILIS
4
Q
1927: GERARD DOMAGK discovered what
A
- Prontosil red, a coal-tar dye for staining
leather, had antibiotic properties - treat streptococcus infections
- active ingred: sulphanilamide
5
Q
1928: The first antibiotic, penicillin, discovered by Alexander Fleming
A
- S. aureus with mould that killed staphylococcus
- mould: Penicillium notatum, which produced penicillin G – diffused into agar – lysed bacteria
6
Q
Florey & Heatley
A
- improved penicillin
7
Q
1944: next was streptomycin
A
TB drug
8
Q
Broad spectrum
A
- inhibits/kills a broad range of microbes
- Tetracycline inhibits Gram-ve, Gram+ve, Chlamydia, Rickettsia
9
Q
Narrow spectrum
A
- inhibits/kills narrow range of microbes
- specificity due to the differences in their cell envelope structures
10
Q
Static agents
A
- growth is inhibited but no killing occurs
- upon removal of the agent the microbe will recover and resume growth
11
Q
Chloramphenicol static or cidal
A
bacteriostatic
12
Q
Cidal agents
A
- cidal agents result in irreversible microbe death, some cause cell lysis
13
Q
Penicillins static or cidal
A
bactericidal
14
Q
Antimicrobial drugs must be selectively toxic bc?
A
- kill or inhibit microbial pathogen
- damage host as little as possible
15
Q
§ toxic dose:
A
dose at which drug becomes too toxic for the host
16
Q
therapeutic dose:
A
dose needed to treat the infection
17
Q
Therapeutic Index
A
Therapeutic dose
18
Q
The ____ the therapeutic index, the better the chemotherapeutic agent
A
larger
19
Q
targets of antibiotic action
A
- Inhibitors of protein synthesis
- Inhibitors of cell wall synthesis
- Metabolic antagonists/antimetabolites
- Inhibitors of DNA/RNA synthesis
- Cell membrane disruption
20
Q
- Inhibitors of protein synthesis
A
- Selective toxicity is fairly good, they target bacterial ribosomes, not eukaryotic ribosomes
- aminoglycosides
- tetracyclines
- macrolides
- chloramphenicol
21
Q
aminoglycosides
A
- cidal
- bind to 30S subunit of ribosome, cause misreading of genetic code
- streptomycin
- Broad
- mainly aerobic Gm –ve’s
22
Q
tetracyclines
A
- static
- bind to 30S subunit of the ribosome
- tetracycline, doxycycline
- Broad - bacteria
23
Q
macrolides
A
- static
- bind to 23S rRNA of 50S subunit
- erythromycin
- broad (good for anaerobes)
24
Q
chloramphenicol
A
- static
- bind to 23S rRNA of 50S subunit
- chloramphenicol
- broad (most bacteria)
25
Broad Inhibitors of protein synthesis
Tetracyclines, macrolides, chloramphenicol
26
2. Inhibitors of cell wall synthesis
* Selective toxicity excellent, they target bacterial cell wall which is not present in eukaryotic cells
* penicillins - cidal - inhibit transpeptidations enzymes - penicillin G narrow - ampicillin braod
27
penicillins
(β-lactams)
* cidal
* inhibit transpeptidation enzymes (=penicillinbinding proteins or PBPs) involved in cross-linking peptidoglycan cell wall
* penicillin G, methicillin --> narrow (Gm+ve only)
* ampicillin, piperacillin--> broad (Gm+ve, & some Gm-ve)
28
Penicillins contain β-lactam ring, what does it do?
* resembles the terminal Dalanyl-D-alanine of the peptides
* Thus penicillins block cross-link formation
* Growing cell wall becomes less able to resist osmotic pressure - penicillins lyse growing cells
29
Semisynthetic penicillins
* to overcome limitations with natural
* New side chains added to β-lactam ring
* Advantages: broader spectrum of activity, acid stability so can be taken orally, resistance to some penicillinases
30
Natural penicillins produced by
Penicillium fungus (penicillin G,
penicillin V, active against Gram
positives, have limitations
* Pen G destroyed by stomach acid, so must be given by injection
* Penicillin-resistance via penicillinases soon developed
31
penicillin G, penicillin V B/N
narrow (Gm+ve only), G is acid-sensitive, penicillinase-sensitive
32
[B/N] ampicillin
broad, (Gm+ve and Gm – ve), acid-stable
33
[B/N]
narrow (Gm-ve including *Ps. aeruginosa*)
34
[B/N] methicillin
narrow, anti-*Staphylococcus* (MRSA)
35
[B/N] piperacillin
extended spectrum (many Gm+ & Gm-ve, resistant to many but not all penicillinases)
36
cephalosporins (β-lactams) characteristics
* Cidal
* MoA: contain βlactam ring
* cefalexin, **cephalothin**,cefoxitin
* broad (Gm+ve, some Gmve), useful if penicillin allergy
37
vancomycin characeristics
* Cidal
* MoA: inhibits transpeptidation, binds to D-ala-Dala so differs from penicillins (its not accessible)
* vancomycin
* narrow (Gm+ve), drug of last resort in some cases e.g. MRSA, enterococci. *ototoxic, nephrotoxic
38
3. Metabolic antagonists/antimetabolites
* Humans don't synthesise folic acid
* sulfonamides (e.g. SMX) inhibit folic acid synthesis
* trimethoprim blocks later step in folate cycle
* high synergism: less of each drug needed in combination than when alone
* THF needed to form DNA bases (A, G, T) and methionine in bacteria
39
high synergism:
less of each drug needed in combination than when alone
40
4. Inhibition of nucleic acid synthesis
* Poor selective toxicity because bacteria and eukaryotes have similar nucleic acid synthesis pathways – but still very useful agents
* quinolones and fluoroquinolones (synthetic drugs)
* rifampin/rifampicin
41
42
rifampin/rifampicin
* cidal
* inhibits RNA polymerase: blocks mRNA synthesis
* rifampicin
* narrow, used for TB, leprosy, and some Gm-ves
43
5. Cell membrane disruption
* Poor selective toxicity as bacterial and human membranes are very similar in
structure
* polymyxins
44
polymyxins characteristics
* cidal
* Disrupt plasma membrane, detergent-like activity
* polymyxin B, polymyxin E = colistin
* Narrow, topical use for Gm-ve’s e.g. Ps. aeruginosa Colistin is drug of last resort for multiply-antibiotic-resistant Gm-ve’s
45
polymyxins tox and fact
* High toxicity, kidney damage, neurotoxicity * Drugs of last resort for some multi-resistant Gram negative bacteria e.g. Ps. aeruginosa, Klebsiella pneumoniae
46
3. Metabolic antagonists/antimetabolites info
* structurally similar to enzyme substrate, so compete with metabolite
* block enzyme activity, thus block a metabolic pathway
* can have good selective toxicity as host lacks pathway, or host enzyme differs from bacterial enzyme
* sulfonamides (sulfa drugs)
* trimethoprim (synthetic drug)
47
Sulfonamides (sulfa drugs)
* static
* inhibit folic acid synthesis by competing with pABA
* sulfanilamide, sulfamethoxazole
* broad
48
trimethoprim (synthetic drug)
* static
* inhibits folic acid synthesis by inhibiting enzyme DHF reductase
* trimethoprim (often used in combination with a sulfonamide as synergistic* )
* broad, Tp/Su= Cotrimoxazole combination is widely used
