7.0 Chemotherapy Flashcards Preview

MedST IB: Mechanisms of Drug Action (MoDA) > 7.0 Chemotherapy > Flashcards

Flashcards in 7.0 Chemotherapy Deck (80)
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1
Q

Aciclovir [acyclovir]

A
  • <b>Class</b> = Purine analogue<br></br>- <b>Target</b> = Viral DNA polymerase<br></br>- <b>Mechanism</b> = Lacks the 3-OH group required for additional nucleotide polymerisation<br></br>- <b>Steps</b>:<br></br>1) Taken up by cell and monophosphorylated by herpes virus thymidine kinase<br></br>2) Cellular enzymes then convert it to triphosphate<br></br>3) Aciclovir triphosphate <b>competitively + permanently inhibits with viral DNA pol</b><br></br>4) Also incorporated into growing chain but cannot continue adding more nucleotides because it aciclovir lacks the 3- OH group<br></br>- <b>Info</b>:<br></br>Selective for viral infected cells because:<br></br>1) Only virally infected cells have thymidine kinase (for monophosphorylation)<br></br>2. Drug preferentially binds to virally encoded DNA pol. (30x stronger bond on viral cf. host)<br></br>-<b>Resistance</b>:<br></br>Viral thymidine kinase changes substrate sensitivity thus does not monophosphate acyclovir
2
Q

Amantadine

A
  • <b>Class</b> = Antiinfluenza drug<br></br>- <b>Target</b> = <br></br>1) M2 channel protein<br></br>2) HA processing<br></br>- <b>Mechanism</b> = <br></br>1) Blocks function of M2 channel → prevents uncoating of virus<br></br>2) Interferes with HA processing → ↓ binding to host (HA needed to bind to sialic acid)<br></br>- <b>Steps</b>: <br></br>- <b>Info</b>:<br></br>Used as prophylaxis or anti-influenza A<br></br>Not effective against influenza B
3
Q

Amoxicillin

A
  • <b>Class</b> = Antibiotic (beta-lactam)<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Inhibits Peptidoglycan transpeptidase<br></br>- <b>Steps</b>: <br></br>1) PG transpeptidase mistakes amoxicillin for an uncrossed PG chain terminatinf in D-Ala-D-Ala<br></br>2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which <b>the beta-lactam ring has opened</b><br></br>3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis<br></br>4) Causes cell lysis because of continued activity of autolysins<br></br>- <b>Info</b>:<br></br>Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics<br></br>Often combined with <b>clavulanic acid</b> (beta-lactamase inhibitor)
4
Q

Amphotericin B

A
  • <b>Class</b> = Polyene (antifungal)<br></br>- <b>Target</b> = Ergosterol in fungal plasma membrane<br></br>- <b>Mechanism</b> = Binds to ergosterol → pore formation<br></br>- <b>Steps</b>:<br></br>Preferentially binds to egosterol (in fungal membranes) as opposed to cholesterol (in human plasma membrane) → selectivity<br></br>Pore formation → ion + macromolecule leakage <br></br>- <b>Info</b>:<br></br>Ergosterol is also found in Leishmania (parasite)
5
Q

Anastrozole

A
  • <b>Class</b> = Hormone therapy (anticancer)<br></br>- <b>Target</b> = Aromatase<br></br>- <b>Mechanism</b> = Inhibitor<br></br>- <b>Steps</b>:<br></br>• Aromatase = enzyme in the oestrogen biosynthetic pathway that converts androgen precursor to estradiol<br></br>• Inhibition of this enzyme ⟶ ↓ oestogen <br></br>- <b>Info</b>:<br></br>Used instead of, or after, treatment with tamoxifen<br></br>Also used in post-menopausal women with breast CA to prevent formation of oestrogens at peripheral sites such as muscle and fat
6
Q

Artemisinin

A
  • <b>Class</b> = Antimalarial <br></br>- <b>Target</b> = -<br></br>- <b>Mechanism</b> = Less well known <br></br>- <b>Steps</b>: <br></br>?Production of reactive oxygen radicals using peroxide bridge?<br></br>?Inhibition of parasite electron transport chain?<br></br>?Inhibits parasite SERCA pump?<br></br>- <b>Info</b>:<br></br><b>Rapid action</b><br></br>Also inhibits development of oocytes in mosquitos
7
Q

Cephalosporin

A
  • <b>Class</b> = Antibiotic (beta-lactam)<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Inhibits Peptidoglycan transpeptidase<br></br>- <b>Steps</b>: <br></br>1) PG transpeptidase mistakes cephalosporin for an uncrossed PG chain terminatinf in D-Ala-D-Ala<br></br>2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which <b>the beta-lactam ring has opened</b><br></br>3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis<br></br>4) Causes cell lysis because of continued activity of autolysins<br></br>- <b>Info</b>:<br></br>Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics
8
Q

Cetuximab

A
  • <b>Class</b> = Monoclonal antibody (anticancer)<br></br>- <b>Target</b> = EGFR<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>EGFR = RTK<br></br>Binding of specific ligand ⟶ conformational changes ⟶ ↑ RTK activity ⟶ ↑ cell activity such as proliferation and differentiation<br></br>Abnormal EGFR expression involved in many malignancies<br></br>Inhibition achieved by preventing ligand binding with anti-EGFR antibody<br></br>- <b>Info</b>:<br></br>Human-mouse chimeric monoclonal antibody<br></br>Cetuximab can reverse the resistance of colorectal cancers to topoisomerase inhibitors<br></br>Used in combination with irinotecan (top. inhibitor)
9
Q

Chloramphenicol

A
  • <b>Class</b> = Antibiotic<br></br>- <b>Target</b> = 50S ribosomal subunit<br></br>- <b>Mechanism</b> = Blocks aminoacyl-tRNA interaction with P site of peptidyl transferase centre<br></br>- <b>Steps</b>: <br></br>- <b>Info</b>:<br></br>Bacteriostatic
10
Q

Chloroquine

A
  • <b>Class</b> = Antimalarial<br></br>- <b>Target</b> = Haem polymerisation by plasmodium spp<br></br>- <b>Mechanism</b> = Inhibits formation of hemozoin<br></br>- <b>Steps</b>: <br></br><b>Events during Plasmodium erythrocytic cycle:</b><br></br>-Plasmodium in RBCs use haemoglobin as nitrogen source ⟶ accumulation of heme<br></br>-Could accumulate to toxic levels (up 200-500mM)<br></br>- This causes production of reactive oxygen species ⟶ harming the parasite<br></br>- Parasites ∴ polymerise toxic heme ⟶ non-toxic hemozoin (in food vacuole)<br></br><b>Mechanism of Chloroquine:</b><br></br>Inhibits formation of hemozoin via 2 methods:<br></br>1. Inhibiting polymerase<br></br>2. Complexation of heme<br></br>It also ↑ pH in food vacuole <br></br>- <b>Info</b>:<br></br>-<b>Resistance</b>:<br></br>Parasites achieve resistance by efflux of cholorquine out of food vacuoles
11
Q

Ciprofloxacin

A
  • <b>Class</b> = Antibiotic (fluoroquinolone)<br></br>- <b>Target</b> = Topoisomerases (Type II)<br></br>- <b>Mechanism</b> = Inhibits <b>DNA gyrase</b> and topo IV (both type II topoisomerases)<br></br>- <b>Steps</b>: <br></br>1) Type II topoisomerases cleave both strands of DNA in an ATP dependent manner (DNA gyrase can supercoild DNA, Topo IV cannot)<br></br>2) Fluoroquinolones affect double strand cleavage/re-ligation cycle<br></br>3) Build up of complexes → effect on replication forks → cell death<br></br>- <b>Info</b>:<br></br>Used in UTI, osteomyelitis, gastroenteritis
12
Q

Cisplatin

A
  • <b>Class</b> = Platinum compound (anticancer)<br></br>- <b>Target</b> = N7 atoms of guanine and adenine in tumour cells<br></br>- <b>Mechanism</b> = <br></br>Covalently binds DNA ⟶ <b>intrastrand cross-linking</b> ⟶ prevents DNA replication<br></br>- <b>Steps</b>: <br></br>• Only active in cis form<br></br>• Small size ⟶ crosslinking occurs between two neigbouring pGpG (intrastrand crosslinking)<br></br>• This induces a major bend in dsDNA ⟶ changes in major groove<br></br>• This (along with physical block provided by platinum adduct) ⟶ inhibition of DNA pol. ⟶ inhibition of DNA replication<br></br>- <b>Info</b>:<br></br>Used in sarcomas, some carcinomas (sc lung cancer, ovarian), lymphomas and germ cell tumours (large improvement in testicular CA treatment)<br></br><b>IV administration</b> (no bioavailability if oral)<br></br>Inactivated by reastions with SH groups in glutathione and metallothioneins<br></br>- <b>Side effects</b> = renal toxicity + bone marrow suppression
13
Q

Clavulanate

A

-<b>Class</b>: Beta-lactamase inhibitor<br></br>-<b>Target</b>: Beta-lactamase<br></br>-<b>Mechanism</b>: forms a slowly hydrolysing acyl enzyme intermediate with Beta-lactamase to inhibit the enzyme - suicide substrate<br></br><br></br>NO EFFECT ON B TYPE BETA LACTAMASE<br></br>-<b>Info</b>:<br></br>-used with amoxicillin to overcome Beta-lactamase induced resistance to Beta-lactam antibiotics. The combination of amoxicillin with clavulanate is Augmentin/co-amoxiclav

14
Q

Co-trimoxazole

A

”- <b>Class</b> = Combination drug (sulfamethoxazole + trimethoprim)<br></br>- <b>Target</b> = Folate synthesis (DHPS + DHFR)<br></br>- <b>Mechanism</b> = <br></br>Sulfamethoxazole → inhibits DHPS<br></br>Trimethoprim → inhibits DHFR<br></br>- <b>Steps</b>: <br></br>- <b>Info</b>:<br></br>Link with Steven Johnson syndrome<div><br></br></div><div><img></img></div>”

15
Q

Cyclophosphamide

A
  • <b>Class</b> = Nitrogen mustard (anticancer)<br></br>- <b>Target</b> = DNA<br></br>- <b>Mechanism</b> = <b>Covalently</b> binds DNA and prevents DNA replication + gene expression<br></br>- <b>Steps</b>: <br></br>Needs to be metabolised by cytochrome p450 to be activated (cyclophosphamide → phophoramide)<br></br>1) Binds to DNA + causes alkylation<br></br>2) Causes <b>cross-linking</b><br></br>3) Can cause CG → AT transition<br></br>4) Basically prevents effective DNA replication and gene expression<br></br>- <b>Info</b>:<br></br>Oral admin<br></br>Most commonly used alkylating agent<br></br>Broad application (lymphoid/ breast/ lung/ ovary CA)<br></br>Used with other drugs to reduce resistance
16
Q

Daunomycin

A
  • <b>Class</b> = Antibiotic (polycyclin)<br></br>- <b>Target</b> = DNA template<br></br>- <b>Mechanism</b> = Non-covalent binding to DNA template<br></br>- <b>Steps</b>: <br></br>Inserts between adjacent base pairs<br></br>Intercalation → affects dimensions of major and minor grooves ⟶ affects DNA/RNA pol interactions ⟶ prevention of normal replication and transcription<br></br>Prevents DNA from being resealed<br></br><br></br>- <b>Info</b>:<br></br>Planar structure
17
Q

D-cycloserine

A
  • <b>Class</b> = Antibiotic<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Mimics D-ala<br></br>- <b>Steps</b>: <br></br>1) Inhibits L-alanine racemase<br></br>2) Inhibits D-ala D-ala synthase<br></br>3) Inhibits ligase (that joins to UDP-NAG)<br></br>- <b>Info</b>:<br></br>2nd class drug anti-TB
18
Q

Erlotinib

A
  • <b>Class</b> = Small molecule inhibitor (quinazoline derivative)<br></br>- <b>Target</b> = EGFR<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>:<br></br>EGFR = RTK<br></br>Inhibition → ↓ proliferation and division <br></br>- <b>Info</b>:<br></br>Orally active<br></br>Potent<br></br>Selective<br></br>Toxicity → skin rashes + diarrhoea<br></br>Good in pancreatic and advanced NSCLC
19
Q

Erythromycin

A
  • <b>Class</b> = Antibiotic (Macrolide)<br></br>- <b>Target</b> = 50s ribosomal subunit<br></br>- <b>Mechanism</b> = Binds to polypeptide export tunnel on 50S → prevents elongation<br></br>- <b>Steps</b>: <br></br>1) Interacts with 23S rRNA in export tunnel<br></br>2) Allows 6-8 oligopeptidyl-tRNA build up before elongation is blocked<br></br>3) Causes premature termination<br></br>- <b>Info</b>:<br></br>Bacteriostatic or bacteriocidal (depends on dose + bacterial species/density)<br></br>-<b>Resistance mechanism:</b><br></br>-methylation of adenine in 23S rRNA of 50S subunit by N-methyltransferase to prevent binding of macrolide antibiotics.
20
Q

Etoposide

A
  • <b>Class</b> = Topoisomerase II inhibitor<br></br>- <b>Target</b> = Topoisomerase II (human)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Inhibition of type II topoisomerase in tumour cells ⟶ torsional stress on the DNA during DNA replication and transcription ⟶ genomic instability and impaired tumour cell proliferation <br></br>- <b>Info</b>:<br></br>Used in the treatment of lung cancer, testicular cancer, lymphoma
21
Q

Fansidar

A

”- <b>Class</b> = Combination drug (sulfadoxin + Pyrimethamine)<br></br>- <b>Target</b> = Folate synthesis (DHPS + DHFR)<br></br>- <b>Mechanism</b> = <br></br>Sulfadoxin → inhibits DHPS<br></br>Pyrimethamine → inhibits DHFR<br></br>- <b>Steps</b>: <br></br>- <b>Info</b>:<div><br></br></div><div><img></img></div>”

22
Q

Fluconazole

A
  • <b>Class</b> = Triazole (antifungal)<br></br>- <b>Target</b> = Enzymes involved with ergosterol synthesis<br></br>- <b>Mechanism</b> = Inhibition <br></br>- <b>Steps</b>: <br></br>↓ ergoesterol → alters fluidity of membrane → alters permeability + activity of membrane associated enzymes<br></br>- <b>Info</b>:<br></br>-<b>Resistance</b>:<br></br>1) Alterations in the amount of enzymes involved with ergosterol synthesis<br></br>2) Efflux
23
Q

Fosfomycin

A
  • <b>Class</b> = Antibiotic<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Mimics phosphoenolpyruvate<br></br>- <b>Steps</b>: <br></br>1) Inhibits pyruvryl transferase<br></br>- <b>Info</b>:
24
Q

Fusidic acid

A
  • <b>Class</b> = Antibiotic <br></br>- <b>Target</b> = Elongation factors<br></br>- <b>Mechanism</b> = Inhibits protein synthesis<br></br>- <b>Steps</b>: <br></br>1) Binds to and inhibits elongation factor G<br></br>- <b>Info</b>:
25
Q

Goseraline

A
  • <b>Class</b> = Hormone therapy (anticancer)<br></br>- <b>Target</b> = GnRH receptor<br></br>- <b>Mechanism</b> = GnRH analogue → biochemical castration<br></br>- <b>Steps</b>:<br></br>• GnRH ⟶ ↑ LH + FSH ⟶ ↑ testosterone secretion<br></br>• Testosterone can stimulate prostate cancer<br></br>• Normal secretion of GnRH is pulsatile<br></br>• Continuous GnRH ⟶ immediate ↑ LH + FSH ⟶ complete inhibition of their release<br></br>Goseraline effectively does this (causes biochemical castration) <br></br>- <b>Info</b>:
26
Q

Imatinib

A
  • <b>Class</b> = Small molecule inhibitor (anticancer)<br></br>- <b>Target</b> = BCR-ABl<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>:<br></br> BCR-ABl = RTK<br></br>- <b>Info</b>:<br></br>• Most chronic myeloid leukaemia patients carry the philadelphia chromosome, resulting from a reciprical exchange of the long arms of chromosomes 9 and 22 - this generates a fusion gene, leading to a BCR-ABL protein with tyrosine kinase activity. Imatinib blocks this activity to prevent excessive proliferation<br></br>• Can also inhibit c-kit tyrosine kinase activity, the encoding gene of which is overexpressed in gastrointestinal stomal tumours (GISTs)<br></br>Marketed as Gleevec
27
Q

Isoniazid

A
  • <b>Class</b> = Antimicrobial<br></br>- <b>Target</b> = Mycolic acid synthesis<br></br>- <b>Mechanism</b> = Inhibition of mycolic acid synthesis<br></br>- <b>Steps</b>:<br></br>M.tuberculosis has significant intrinsic resistance to many antimicrobial compounds compared to other bacteria due to the high mycolic acid content in the lipid bilayer<br></br>- <b>Info</b>:<br></br>-first line treatment for tuberculosis against M. tuberculosis.<br></br>-other bacteria, which do not feature mycolic acid, have a high intrinsic resistance to this drug
28
Q

Leucovorin

A
  • <b>Class</b> = Folate source<br></br>- <b>Target</b> = -<br></br>- <b>Mechanism</b> = Provides a metabolic equivalent to folate<br></br>- <b>Steps</b>: <br></br>• Can be converted to reduced folic acid derivatives (e.g. tetrahydrofolate) ∴ has a vitamin activity equivalent to folic acid<br></br>• ∵ does not rely on DHFR, it is unaffected by methotrexate<br></br><br></br>- <b>Info</b>:<br></br>Selectively is achieved ∵ proliferating tumour cells have much higher tetrahydrofolate requirement, thus leucovorin doesn’t help them as much as it does healthy cells
29
Q

Lomustine

A
  • <b>Class</b> = Nitrosurea (anticancer)<br></br>- <b>Target</b> = DNA <br></br>- <b>Mechanism</b> = Not well understood<br></br>- <b>Steps</b>: <br></br>Cause <b>alkylation</b> and <b>carbamoylation</b><br></br>Can produce inter strand <b>cross-links</b><br></br>Bind preferentially to <b>guanine</b><br></br>- <b>Info</b>:<br></br>Oral administration<br></br>Lipophilic → good brain penetration → Important for <b>brain tumours</b><br></br>-<b>Side effects</b>:<br></br>↓WBC, ↓ Platelets + damage organs
30
Q

Melarsoprol

A
  • <b>Class</b> = Arsenic compound (anti-parasitic)<br></br>- <b>Target</b> = Lipoic acid dependent enzymes<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Enzymes inhibited = 2-oxo-decarboxylase and pyruvate dehydrogenase<br></br><b>Affects ATP synthesis</b><br></br>Melarsoprol = prodrug (drug = melarsan oxide)<br></br>- <b>Info</b>:<br></br>Specific for <b>Leishmaniasis</b>
31
Q

Methicillin

A
  • <b>Class</b> = Antibiotic (beta-lactam)<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Inhibits Peptidoglycan transpeptidase<br></br>- <b>Steps</b>: <br></br>1) PG transpeptidase mistakes methicillin for an uncrossed PG chain terminating in D-Ala-D-Ala<br></br>2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which <b>the beta-lactam ring has opened</b><br></br>3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis<br></br>4) Causes cell lysis because of continued activity of autolysins<br></br>- <b>Info</b>:<br></br>Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics<br></br>Introduced following emergence of penicillin-resistant gram positive bacteria (has a bulky 2,6-dimethoxybenzoyl substitute to reduce the susceptibility of the intermediate enzyme to hydrolysis)<br></br><b>-Resistance mechanism:</b> <br></br><b>MecA</b> gene which (encodes a beta-lactam resistance bi-functional transpeptidase/transglycosylase)<br></br><b>Fem genes</b> (contribute to resistance by adding a cross bridge to PG strands, which allows PG to act as a better substrate for MecA transpeptidase)
32
Q

Methotrexate

A

”- <b>Class</b> = Folic acid antagonist<br></br>- <b>Target</b> = DHFR (dihydrofolate reductase)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Disruption of nucleotide synthesis ⟶ disruption of DNA replication<br></br>- <b>Info</b>:<br></br>↑↑ use of methotrexate ⟶ toxicity to normal cells (leucovorin can help with this)<div><br></br></div><div><img></img></div>”

33
Q

Miconazole

A
  • <b>Class</b> = Imidazole (antifungal)<br></br>- <b>Target</b> = Enzymes involved with ergosterol synthesis<br></br>- <b>Mechanism</b> = Inhibition <br></br>- <b>Steps</b>: <br></br>↓ ergoesterol → alters fluidity of membrane → alters permeability + activity of membrane associated enzymes<br></br>- <b>Info</b>:<br></br>Also works on parasites (Leishmania)
34
Q

Mitomycin C

A
  • <b>Class</b> = Antibiotic (aziridine containing antibiotic/anticancer)<br></br>- <b>Target</b> = DNA template<br></br>- <b>Mechanism</b> = Covalent bonding<br></br>- <b>Steps</b>: <br></br>Alkylates DNA (Preferentially at guanine bases at GC positions in complementary DNA strands)<br></br>Results in the <b>cross-linking</b> of two guanine bases, one in each strand of the double helix ⟶ prevents strand separation during DNA replication and transcription <br></br>- <b>Info</b>:<br></br>Can also be used as an anticancer medication<br></br>More reactive in low oxygen conditions
35
Q

Mitoxantrone

A
  • <b>Class</b> = Anthracyclin (anti-cancer)<br></br>- <b>Target</b> = DNA<br></br>- <b>Mechanism</b> = Non-covalent binding<br></br>- <b>Steps</b>: <br></br>Intercalation causes unwinding of the helix → DNA + RNA pol affected → ↓ transcription and replication<br></br>- <b>Info</b>:<br></br>This is a modified version of <b>doxorubicin</b> - it lacks the hydroxyquinone moiety therefore does not produce the free radicals that caused all the side effects (cardiac shit)<br></br>Also inhibits <b>topoisomerase II</b>
36
Q

Nevirapine

A
  • <b>Class</b> = Reverse transcriptase inhibitor (non-nucleoside)<br></br>- <b>Target</b> = HIV reverse transcriptase <br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Binds to target enzyme near catalytic site and denatures it<br></br>- <b>Info</b>:<br></br>Component of HAART<br></br>Reverse transcriptase activity is early in replication cycle, therefore this drug only has effect early
37
Q

Oseltamivir

A
  • <b>Class</b> = Anti-influenza drug<br></br>- <b>Target</b> = Neuraminidase<br></br>- <b>Mechanism</b> = Inhibitor<br></br>- <b>Steps</b>: <br></br>Inhibits NA → ↑ viral aggregation + ↓ release from host<br></br>- <b>Info</b>:<br></br>Oseltamivir is an <b>ethyl ester pro-drug</b><br></br>Cleaved by esterases in the plasma + gut on adsorption
38
Q

Penicillin

A
  • <b>Class</b> = Antibiotic (beta-lactam)<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Inhibits Peptidoglycan transpeptidase<br></br>- <b>Steps</b>: <br></br>1) PG transpeptidase mistakes penicillin for an uncrossed PG chain terminating in D-Ala-D-Ala<br></br>2) Active site serine attacks the beta lactam ring of the antibiotic → acyl-enzyme intermediate in which <b>the beta-lactam ring has opened</b><br></br>3) This resulting covalent penicilloyl enzyme is very slow to hydrolyse → ↓↓↓ further PG synthesis<br></br>4) Causes cell lysis because of continued activity of autolysins<br></br>- <b>Info</b>:<br></br>Only proliferating cells in which autolysins are active are sensitive to beta lactam antibiotics
39
Q

Prednisone

A
  • <b>Class</b> = Hormone therapy (steroid)<br></br>- <b>Target</b> = Glucocorticoid receptor<br></br>- <b>Mechanism</b> = Agonist<br></br>- <b>Steps</b>: <br></br>• Used in the treatment of inflammatory and autoimmune conditions<br></br>• Has a lymphocytic effect and is useful against leukaemias<br></br><br></br>- <b>Info</b>:<br></br>Administered as prodrug prednisone, and is converted to active prednisolone by the liver
40
Q

Pyrimethamine

A

”- <b>Class</b> = Antiparasitic<br></br>- <b>Target</b> = DHFR (dihydrofolate reductase)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>This inhibition traps folate co-enzyme in its useless form (dihydrofolate)<br></br>Leads to <b>rapid depletion</b> of tetrahydrofolate<br></br>- <b>Info</b>:<br></br>Can be combined with sulfadoxin (Fansidar)<div><br></br></div><div><img></img></div>”

41
Q

Rifampin

A
  • <b>Class</b> = Antibiotic<br></br>- <b>Target</b> = Beta subunit on DNA-dependent RNA polymerase<br></br>- <b>Mechanism</b> = Inhibition of RNA synthesis<br></br>- <b>Steps</b>: <br></br>1) <b>Non-covalent binding</b> to an allosteric site on the β subunit of the DNA-dependent RNA polymerase → blocks elongation of RNA chain <br></br>2) Directly blocks the elongating RNA chain at the di- or tri-nucleotide stage → inhibits new RNA synthesis<br></br><b>But synthesis in progress at the time of drug exposure is not affected</b><br></br>- <b>Info</b>:<br></br>Derivative of Rifamycin B<br></br>Binding ratio = one mole drug : one mole enzyme
42
Q

Saquinavir

A
  • <b>Class</b> = HIV protease inhibitor<br></br>- <b>Target</b> = HIV Asp protease<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>1) HIV asp protease cleaves translated gag protein → mature protein<br></br>2) Lack of functioning Asp. protease means that virus is not infectious<br></br>- <b>Info</b>:<br></br>Mutation in enzymes → ↓ interaction between enzyme and inhibitor
43
Q

Streptomycin

A
  • <b>Class</b> = Antibiotic (aminoglycoside)<br></br>- <b>Target</b> = 30S subunit of ribosome<br></br>- <b>Mechanism</b> = <b>Prevents initiation</b><br></br>- <b>Steps</b>: <br></br>1) Binds near the A site for aminoacyl-tRNA binding<br></br>2) Decreases fidelity of translation<br></br>- <b>Info</b>:<br></br><b>Bacteriocidal</b> (because reduces fidelity of proteins made, therefore wrong aminoacid → leaky protein etc)<br></br>-<b>Resistance mechanism:</b><br></br>-covalent modification of OH and NH2 residues that allow specific binding to 16S rRNA of 30S subunit. 3 types of modication: N-acetylation, O-phosphoryl trasnfer and O-adenylyl transfer.<br></br>-reduced number of porins or modifications of LPS layer in Pseudomonas aeruginosa reduces uptake. Mutations in active tranporters required for uptake from periplasm<br></br>-active efflux
44
Q

Sulfadoxin

A

”- <b>Class</b> = Sulfonamide<br></br>- <b>Target</b> = DHPS (dihydropteroate synthase)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Shuts off de-novo synthesis of folate (nneded for thymidine synthesis)<br></br><b>causes a slow killing mechanism</b><br></br>- <b>Info</b>:<br></br>Can be combined with prymethamine (Fansidar)<br></br>Drug analogue = sulfamethoxazole (antibiotic)<br></br>P-aminobenzoate analogue<div><br></br></div><div><img></img></div>”

45
Q

Sulfamethoxazole

A

”- <b>Class</b> = Sulfonamide<br></br>- <b>Target</b> = DHPS (dihydropteroate synthase)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Shuts off de-novo synthesis of folate (needed for thymidine synthesis)<br></br><b>causes a slow killing mechanism</b><br></br>- <b>Info</b>:<br></br>Can be combined with trimethoprim (co-trimoxazole)<br></br>P-aminobenzoate analogue<div><br></br></div><div><img></img></div>”

46
Q

Suramin

A
  • <b>Class</b> = Trypanocidal drug<br></br>- <b>Target</b> = Glycerol-3-phosphate oxidase + NAD⁺-dependent glycerol-3-phosphate dehydrogenase<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>Inhibition of the above enzymes → interference with reoxidation of NADH → ↓ ATP synthesis<br></br>- <b>Info</b>:
47
Q

Tamoxifen

A
  • <b>Class</b> = Hormonal therapy (anticancer)<br></br>- <b>Target</b> = Oestrogen receptor <br></br>- <b>Mechanism</b> = Inhibitor <br></br>- <b>Steps</b>: <br></br>• Competitively binds to oestrogen receptor (lower affinity than oestrogen)<br></br>• Once bound ⟶ complex translocates to nucleus ⟶ attenuation of oestrogen-responsive genes involved in development and growth of breast CA<br></br>- <b>Info</b>:<br></br>70% of breast CA is +ve for oestrogen + progesterone receptor ∴ responsive to this therapy<br></br>Tamoxifen can exert oestrogen agonist effect in other tissues (bone and uterus)<br></br><b>Toremifene</b> = tamoxifen analogue without this oestrogen agonist issue
48
Q

Taxol

A
  • <b>Class</b> = Taxane<br></br>- <b>Target</b> = Free tubular dimers<br></br>- <b>Mechanism</b> = Prevents mitosis<br></br>- <b>Steps</b>: <br></br>• Disrupts the equilibrium between free dimers amd microtubules by shifting it in the direction of <b>assembly rather than disassembly</b><br></br>• Leads to the stabilization of ordinary cytoplasmic microtubules and the formation of abnormal bundles of microtubules to inhibit mitosis <br></br>- <b>Info</b>:<br></br>Used in antiproliferative drug eluting stents in coronary angioplasty for the treatment of angina and ischaemic heart disease<br></br>Used in treatment of lung, ovarian, breast, head and neck cancer, and in Kaposi’s sarcoma
49
Q

Tetracycline

A
  • <b>Class</b> = Antibiotic <br></br>- <b>Target</b> = 30S subunit<br></br>- <b>Mechanism</b> = Blocks rotation of aminoacyl-tRNA into A site<br></br>- <b>Steps</b>:<br></br>1) Interacts with Mg²⁺ ion + nucleotides in 16S rRNA of 30S<br></br>2) Does not block initial binding of aminoacyl-tRNA, but <b>blocks subsequent rotation into A site</b><br></br>3) Therefore no bond would be formed and peptide would be released prematurely<br></br>- <b>Info</b>:<br></br>Bacteriostatic<br></br>Shows activity against some protozoa (Plasmodium)
50
Q

Topotecan

A
  • <b>Class</b> = Topoisomerase type I inhibitor<br></br>- <b>Target</b> = Topoisomerase type I (human)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>- <b>Info</b>:<br></br>Used in ovarian and lung CA
51
Q

Trimethoprim

A

”- <b>Class</b> = Antibiotic<br></br>- <b>Target</b> = DHFR (dihydrofolate reductase)<br></br>- <b>Mechanism</b> = Inhibition<br></br>- <b>Steps</b>: <br></br>This inhibition traps folate co-enzyme in its useless form (dihydrofolate)<br></br>Leads to <b>rapid depletion</b> of tetrahydrofolate<br></br>- <b>Info</b>:<br></br>Can be combined with sulfamethoxazole (co-trimoxazole)<div><br></br></div><div><img></img></div>”

52
Q

Valinomycin

A
  • <b>Class</b> = Antibiotic (Ionophore)<br></br>- <b>Target</b> = Cell membrane<br></br>- <b>Mechanism</b> = Disruption of cell membrane<br></br>- <b>Steps</b>: <br></br>Forms a circular structure that coordinates K⁺ ion <br></br>Diffuses across the membrane therefore <b>acts as a K⁺ uniporter</b><br></br>Effect is due to dissipation of transmembrane ion gradients<br></br>This disturbs ion homeostasis and energy metabolism and induce leakage of macromolecules from the bacteria<br></br>- <b>Info</b>:<br></br>Contains 3 repeating units of (L-lactate)- (L-valine)-(D-hydroxyisovalerate)-(D-valine)<br></br><b>Lacks specificity</b> (phospholipid bilayer not only in bacteria)
53
Q

Vancomycin

A
  • <b>Class</b> = Antibiotic (glycopeptide)<br></br>- <b>Target</b> = Cell wall biosynthesis<br></br>- <b>Mechanism</b> = Inhibits Peptidoglycan transpeptidase action<br></br>- <b>Steps</b>: <br></br>1) Vancomycin binds to pentapeptidyl tails in PG repeating units that end in D-Ala-D-Ala<br></br>2) this makes D-Ala-D-Ala terminus unavailable for transpeptidase enzyme<br></br><b>Also reduces availability for the peptidoglycan transglycosylase enzyme</b><br></br>- <b>Info</b>:<br></br>Only proliferating cells in which autolysins are active are sensitive to this antibiotic<br></br>-<b>Resistance mechanism:</b><br></br>-E. faecalis has acquired the <b>Van genes</b>, two tandemly arranged operons. One operon encodes a his-As phosphorelay that activates the second when exposed to antibiotics. The second encodes enzymes that change (D-Ala)5 to (D-lactate)5 in PG pentapeptide to prevent vanc binding.
54
Q

Vinblastine

A
  • <b>Class</b> = Vinca alkaloid<br></br>- <b>Target</b> = Free tubular dimers<br></br>- <b>Mechanism</b> = Antimitotic<br></br>- <b>Steps</b>: <br></br>• Bind to free tubulin dimers ⟶ <b>prevent microtubule assembly</b><br></br>• ∴ disrupt the equilibrium between polymerisation and depolymerisation to inhibit mitosis of tumour cells <br></br>- <b>Info</b>:<br></br>Results in the disappearance of microtubules<br></br>Cause granulocytopenia in animals<br></br>Used in Hodgkin’s lymphoma, non small cell lung cancer, breast cancer and testicular cancer
55
Q

Zanamivir

A
  • <b>Class</b> = Anti-influenza drug<br></br>- <b>Target</b> = Neuraminidase<br></br>- <b>Mechanism</b> = Inhibitor<br></br>- <b>Steps</b>: <br></br>Inhibits NA → ↑ viral aggregation + ↓ release from host<br></br>- <b>Info</b>:<br></br>Zanamivir is an active drug
56
Q

Zidovudine (azidothymidine, AZT)

A
  • <b>Class</b> = Reverse transcriptase inhibitor (Nucleoside)<br></br>- <b>Target</b> = Reverse transcriptase <br></br>- <b>Mechanism</b> = Thymidine analogue → inhibits reverse transcriptase <br></br>- <b>Steps</b>: <br></br>1) Thymidine analogue therefore acts as substrate for reverse transcriptase<br></br>2) Lack the 3’OH group therefore causes termination of elongation<br></br>3) Usually administered with <b>hydroxyurea</b> (this ↓ natural pyriminadine nucleotides thus enhances the effect of AZT)<br></br>- <b>Info</b>:<br></br>Must be phosphorylated by host cell before becoming active<br></br>Reverse transcriptase activity is early in replication cycle, therefore this drug only has effect early<br></br>- <b>Resistance</b>: <br></br>Mutation in enzymes → ↓ interaction between enzyme and inhibitor
57
Q

Define broad spectrum:

A

Effective against both Gram +ve and Gram -ve

58
Q

Define narrow spectrum:

A

Effective against either Gram +ve or Gram -ve

59
Q

Define limited spectrum:

A

Effective against a single organism

60
Q

Define extended spectrum:

A

Chemically modifying drug to extend spectrum

61
Q

Define bacteriostatic:

A

Stop bacteria from growing<br></br>Elimination of bacteria is dependent on human immune system

62
Q

Define bactericidal:

A

Cause cell death → ↓ cell count

63
Q

Define MIC:

A

MIC = Minimum inhibitory concentration<br></br><br></br>Minimum conc. that prevents bacterial growth<br></br><br></br>Measure of effectiveness of bacteriostatic drugs

64
Q

Define MBC:

A

MIC = Minimum bactericidal concentration<br></br><br></br>Minimum conc. that kills bacterial cells<br></br><br></br>Measure of effectiveness of bactericidal drugs

65
Q

Define selective toxicity:

A

Infecting organism is inhibited/killed without damage to host cells

66
Q

Define therapeutic index:

A

Also known as therapeutic ratio<br></br><br></br>Maximum non-toxic dose / minimum effective dose

67
Q

What structure is present in both Gram +ve and -ve cell walls?

A

<b>Peptidoglycan</b> (PG)

68
Q

What is the difference between Gram +ve and -ve cell walls?

A

<b>Gram +ve</b><br></br>- Thicker PG<br></br>- Teichoic acid polymers<br></br><br></br><b>Gram -ve</b><br></br>- Thinner PG<br></br>- Has an outer membrane

69
Q

What types of cross-linking occurs in PG and what is the purpose of cross-linking?

A

Two types of cross linking occur:<br></br><br></br><b>1) Glycan stands</b><br></br>- Enzyme = transglycosylase<br></br><br></br><b>2) Peptide strands</b><br></br>- Enzyme = transpeptidase<br></br><br></br><b>Peptide cross-links → introduce covalent bonds (provides strength + is a structural barrier)</b>

70
Q

Brief overview of PG synthesis

A

UDP + NAG → UDP-NAG → NAM-tripeptide<br></br>NAM-tripeptide → NAM-pentapeptide<br></br><br></br>NAM binds to <b>bactoprenol phosphate</b><br></br>NAG links to NAM → NAG-NAM<br></br>This complex is transporter to outer surface of cell wall<br></br><br></br>On outer surface - PG polymer is formed<br></br><b>PG transglycosylase</b> adds building unit to existing PG<br></br><b>PG transpeptidase</b> cross links these units

71
Q

What is the mechanism of action of peptidoglycan transpeptidases?

A

It is a <b>serine hydrolase</b><br></br>Attacks aminde bond between terminal D-ala₄ D-Ala₅<br></br>D-Ala₅ released as free amino acid<br></br>Intermediate is covalently linked to PG<br></br>Acyl transfer occurs with neighboring peptide → cross-linking

72
Q

What are the two units of bacterial ribosome (70S)?

A

30S<br></br>50S

73
Q

What is the first amino acid for all proteins?

A

<b>Formylmethionine</b>

74
Q

What are the steps for protein synthesis:

A

<b>STAGE 1</b> - Initiation<br></br><br></br><b>1) mRNA binds to 30S</b><br></br>- Needs IF3<br></br><b>2) tRNA-formylmethionine combines with mRNA-30S</b><br></br>- Needs IF1 + IF2 + GTP<br></br><b>3) 50S joins this complex</b><br></br>- GTP hydrolysed and all initiation factors are released<br></br><br></br><b>STAGE 2</b> - Elongation<br></br>Needs elongation factors and GTP<br></br>1) Amino acids are side by side on the 50S<br></br>2) Amino acids get linked by peptide bond (50s has transpeptidyl transferase activity)<br></br>3) tRNAs move along (P → E and A → P)<br></br>4) 30S unit moves along one codon<br></br><br></br>Continues until stop codon

75
Q

In general what is the effect of antibiotics that inhibit protein synthesis?

A

Generally bacteriostatic

76
Q

What are the stages of folate synthesis

A

“<div><img></img></div>”

77
Q

What are the mechanisms for intrinsic (natural) drug resistance?

A

1) Organism lacks receptor for drug<br></br>2) Concentration of drug at the target is inadequate

78
Q

Why are Mycobacterium species resistant to many antimicrobial agents?

A

Due to high content of mycelia acids in a complex lipid layer outside their PG.<br></br><br></br>This layer is impermeable to many drugs

79
Q

What are the tree mechanisms by which bacteria acquire resistance?

A

1) Enzymatic inactivation of drug<br></br>2) Replacement/ amplification/ modification of drug target<br></br>3) Decreased drug uptake or increased efflux

80
Q

How do beta-lactamases achieve resistance to Beta lactams?

A

Beta lactamase is an enzyme (<b>serine enzyme</b>) that hydrolyses the beta lactam ring.