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Chemotherapy Flashcards

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1
Q

Fosfomycin

A

Inhibits MurA, which adds PEP to UDP-NAG to form UDP-NAG-EP.

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2
Q

D-cycloserine

A

Inhibits L-alanine racemase and D-alanine:D-alanine ligase, and MurF which adds D-Ala-D-Ala to UDP-NAM-L-Ala-D-Glu-L-Lys.

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3
Q

Bacitracin

A

Forms a tight complex with Mg2+ and bactoprenol pyrophosphate; inhibits the dephosphorylation to bactoprenol phosphate.

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4
Q

Penicillin, Cephalosporin, Monobactam, Carbapenem

A 
Peptidoglycan transpeptidase (variant of serine hydrolases) mistakes penicillin for a yet to be cross-linked PG chain terminating in D-Ala-D-Ala. This is due to the similarity in configuration of the CO-N bond in penicillin and CO-N bond between D-Ala and D-Ala.
An acyl-enzyme intermediate is still formed, but the acyl group is made of penicilloyl (penicillin with β-lactam ring opened). This acyl-enzyme intermediate is very slow to hydrolyse hence cross-linking is essentially inhibited.
Cell wall autolysins continue to re-shape PG during cell growth and division, however this now induces lysis of the cell since new PG made is unstable.
Hence only proliferating cells, in which autolysins are active, are sensitive to β-lactam antibiotics.
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5
Q

Vancomycin

A

Binds to D-Ala-D-Ala of pentapeptide in peptidoglycan via 5 H-bonds, preventing its cross-linking to a neighbouring pentapeptide in another peptidoglycan strand.
Used against clostridium difficile and Gram-positive cocci.

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6
Q

Extended spectrum cephalosporin

A

Active against Gram-positive bacteria with increased activity against Gram-negative bacteria.
Contains an oxyimino side chain which is more difficult to fit in the active site of β-lactamases.

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7
Q

Tetracycline (Tetracycline family)

A

Tetracycline forms electorstatic interactions with oxygen atoms in internucleotide phosphodiester links in 16S rRNA of the ribosome via a Mg2+ ion. Inhibits movement of aminoacyl tRNA into the A site after EF-Tu-GTP hydrolysis.
Broad-spectrum, first-line drugs against mycoplasma and cholera. Also effective against Plasmodium parasites.

Ribosomal protection proteins can dislodge tetracycline from ribosome.

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8
Q

Chloramphenicol (Amphenicol family)

A

Blocks aminoacyl tRNA binding to 50S subunit of ribosome.
Broad-spectrum antibiotic but use is restricted because of bone marrow suppression. Only for life-threatening infections such as meningitis.

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9
Q

Erythromycin, clarithromycin, azithromycin, tylosin (Macrolide family)

A

Binds to 23S rRNA in 50S subunit, and blocks the polypeptide exit tunnel, physically inhibiting elongation of polypeptide chain.
Similar antibacterial spectrum as penicillin, and is a second-line drug for patients allergic to penicillin.
Can be bacteriostatic or bactericidal.

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10
Q

Streptomycin, gentamycin, kanamycin, pararomycin (Aminoglycoside family)

A

Target 30S subunit of ribosome and decrease fidelity of mRNA translation. So aminoglycosides are bactericidal (others are bacteriostatic).
Streptomycin causes nephrotoxicity and ototoxicity (less for gentamycin).
Used for Gram-negative bacilli/rods.

Most streptococci are resistant because aminoglycosides cannot penetrate the cell. β-lactams disrupt cell membrane to increase passive diffusion of aminoglycoside. Penicillin and gentamycin (specifically) have a synergistic effect against some streptococci.

Note that a bactericidal (e.g penicillin) and bacteriostatic (e.g. tetracycline) will cause antagonism since penicillin only has effect on actively dividing cells.

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11
Q

Linezolid (Oxazolidinone family)

A

Interaction with the 23S ribosomal RNA of the 50S ribosomal subunit. Broad spectrum.

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12
Q

Spectinomycin (Aminocyclitol family)

A

Target 30S subunit of ribosome and inhibits EF-G function.

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13
Q

Clindamycin, lincomycin (Lincosamide family)

A

Targets 23S rRNA of 50S subunit. Binding site overlaps with macrolides and streptogramin B. No need to know function.
Effective against Plasmodium parasites.

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14
Q

Fusidic acid

A

Inhibits EF-G. Narrow spectrum, used against staphylococcal infections.

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15
Q

Synercid

A

Quinupristin + dalfopristin. Binds to 23S rRNA of 50S subunit to prevent polypeptide translocation.

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16
Q

Novobiocin, coumermycin A1 (Aminocoumarin family)

A

Targets GyrB subunit of DNA gyrase.

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17
Q

Ciprofloxacin, gatifloxacin, levofloxacin (Fluoroquinolone family)

A

Inhibits type II DNA topoisomerases (DNA gyrase and topo IV). Caused cleaved dsDNA to accumulate, replication forks are halted, bactericidal.
Ciprofloxacin used against Bacillus anthracis and Pseudomonas.
R-factor encoded quinolone resistance protein (QNR) physically blocks binding of antibiotic.

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18
Q

Rifampin/rifampicin

A

Binds to the DNA/RNA tunnel associated with the β subunit of DNA-dependent RNA polymerase. Physically inhibits RNA chain elongation.

Can block fungal DNA-dependent RNA polymerase, but needs help from polyene antibiotics to get through ergosterol membrane.

Upregulates PXR to increase CYP3A4 production.

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19
Q

Daunorubicin, doxorubicin (Anthracycline family)

A

Intercalates in dsDNA and causes local unwinding. Affects molecular dimensions of major and minor groove, prevents interaction of molecules with DNA necessary for DNA replication and transcription.

Has hydroxyquinone moiety so can generate free radicals which cause lipid peroxidation in cardiac tissue.

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20
Q

Bleomycin

A

Chelates Fe2+, producing a molecule that reacts with O2 to generate reactive radicals, causing single and double stranded breaks in DNA.
Especially toxic to Gram positives and mammalian cells.

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21
Q

Mitomycin C

A

Aziridine-containing antibiotic. Needs to be activated by reduction of the quinone group.
Alkylates guanine bases at GC positions in complementary DNA strands.
Causes cross-linking of two guanine bases, one on each strand, and prevents strand separation during DNA replication and transcription.

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22
Q

Sulfamethoxazole/Sulfadiazine

A

Inhibits bacterial DHPS. DHPS turns pABA into dihydropteroate.
DHPS absent in eukaryotes as we scavenge folate from dietary sources but bacteria have to make it de novo.

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23
Q

Trimethoprim

A

Inhibits bacterial DHFR. DHFR turns FH2 into FH4/THF, which is then converted into 5,10-methylene-FH4, which is used to maked dTMP.
Bacterial and mammalian DHFR has enough structural differences for selective inhibition.

Metabolic bypass: R plasmid-encoded DHPS and DHFR have a much lower binding affinity for the antibiotics than the normal bacterial enzymes.

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24
Q

Co-trimoxazole

A

Sulfamethoxazole + trimethoprim.
Sulfamethoxazole only shuts of de novo folate synthesis. Existing folate levels will take several bacterial generations to decline.
Adding trimethorpim traps folate in the useless FH2 form (5,10-methylene-FH4 becomes FH2 after being used to make dTMP). Rapid depletion of FH4 form.
Use isobologram to show effects of synergisim.

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25
Valinomycin
Made of 3 repeating units of L-Lactate-L-Valine-D-Hydroxyisovalerate-D-Valine. Acts as a K+ uniporter. Has the specificity: Rb+>K+>Na+>Li.
26
Nigercin
Acts as a K+/H+ antiporter.
27
Monensin
Acts as a Na+/H+ antiporter.
28
Gramicidin A
Forms a homodimeric complex in the membrane. Permits diffusion of monovalent cations with diameters up to 5Å. Has the specificity: H+>Rb+>K+>Na+>Li.
29
Polymixin
Amphipathic molecule with a net charge of +5. Binds to negatively charged phosphate heads. Alters permeability of cytoplasmic membrane. All antibiotics that target membranes act to dissipate transmembrane ion gradients and cause macromolecule leakage. An issue is the lack of selectivity as host cells also has a phospholipid bilayer.
30
Amphotericin B, nystatin
Binds and forms holes preferentially in ergosterol, which is found in fungi and parasties' plasma membrane (e.g. Leishmania species), rather than cholesterol.
31
Fluconazole, miconazole
Inhibit enzymes involved in ergosterol biosynthesis. This alters fluidity and hence permeability of the membrane, and activity of membrane-bound enzymes.
32
Melarsoprol
Prodrug becomes melarsen oxide. Contains arsenic, reacts with dithiols in cofactors like lipoic acid and enzymes like pyruvate kinase and PFK, hence inhibiting ATP synthesis. Preferentially toxic for Trypanosoma species which causes sleeping sickness.
33
Suramin
Has no toxic metal atom. Inhibits glycerol-3-phosphate oxidase and glycerol-3-phosphate dehydrogenase. This interferes with the reoxidation of NADH to NAD+ and hence inhibits ATP synthesis. Also used against Trypanosoma species.
34
Chloroquine, mefloquine, primaquine
Trophozoite phase of Plasmodium, in RBCs, digest haemoglobin to obtain amino acids, which happens in the food vacuole. This produces haem as a toxic byproduct (since oxidation of iron in haem causes production of ROS). Parasite polymerises haem into non-toxic haemozoin. Chloroquine inhibits haem polymerisation and raises pH in food vacuole, reducing metabolism. R-factor encoded chloroquine resistance transporter (CRT) causes chloroquine efflux from food vacuole.
35
Artemisinin
Two hypotheses: (1) Endoperoxide bridge breaks and creates free radicals which causes metabolic stress. (2) Inhibition of Plasmodium's PfATP6. This leads to increased intracellular [Ca2+] and cell death.
36
Artemisinin-based Combination Therapies (ACT)
Artesunate + amodiaquine | Artemether + lumefantrine
37
Sulfadoxin
Inhibits Plasmodium DHPS.
38
Pyrimethamine
Inhibits Plasmodium DHFR.
39
Fansidar
Sulfadoxin + pyrimethamine.
40
Proguanil
Prodrug converted to cycloguanil. Inhibits Plasmodium DHFR.
41
RTS,S (Mosquirix)
Vaccine made from CSP protein of Plasmodium, viral envelope protein of Hepatitis B virus, with adjuvant AS01.
42
Amantadine, rimantadine
Block the function of the M2 channel protein, which is needed to acidify the endosome to promote nucleocapsid uncoating. Used for influenza A virus. Not effective against influenza B virus.
43
Oseltamivir/Tamiflu
An ethyl ester prodrug. Inhibits neuraminidase. Enhances viral aggregation and inhibits release from host cells.
44
Zanamivir/Relenza
Inhibits neuraminidase. Enhances viral aggregation and inhibits release from host cells.
45
Ribavirin
Phosphorylated by cellular kinases to ribavirin-MP,DP,TP. Ribavirin-TP directly inhibits INFLUENZA RNA polymerase, and posttranslational capping of the 5′ end of viral mRNA. Ribavirin-MP inhibits IMPDH which is needed for de novo guanosine synthesis. Inhibits GTP and hence DNA/RNA synthesis. Drug is teratogenic, and causes haemolytic anaemia in 10% of patients due to accumulation in erythrocytes.
46
Acyclovir
Guanosine analogue. Monophosphorylated by herpes virus-encoded thymidine kinase. Cellular enzymes then convert it into triphosphate form. Acyclovir-TP inhibits herpes virus DNA polymerase (much higher affinity than for host cell DNA polymerase) Acyclovir-TP can also be added to 3'-OH of a DNA strand, but it lacks a cyclic sugar so has no 3'-OH to add additional nucleotides.
47
Gancyclovir (pencyclovir same MOA)
Guanosine analogue. Monophosphorylated by CMV virus-encoded phosphotransferase. Cellular enzymes then convert it into triphosphate form. Gancyclovir-TP inhibits CMV DNA polymerase. Gancyclovir-TP has a 3'-OH so will permit chain extension.
48
Cidofovir
Cytosine analogue. Phosphorylated by host cell enzymes into cidofovir-DP which inhibits CMV DNA polymerase. Has 3'-OH so will permit chain extension.
49
Idoxuridine
Thymidine analogue. Monophosphorylated by viral thymidine kinase then to triphosphate form by cellular enzymes. Inhibits herpes virus DNA polymerase. Has 3'-OH so will permit chain extension.
50
Trifluridine
Thymidine analogue. Phosphorylated by host cell enzymes into trifluridine-TP. Inhibits herpes virus DNA polymerase. Has 3'-OH so will permit chain extension.
51
Foscarnet
Pyrophosphate analogue, selectively binds DNA polymerase of CMV and herpes simplex virus. Prevents cleavage of pyrophsohpate from nucleoside triphosphate during DNA polymerisation.
52
Nevirapine
NNRTI. Denatures HIV reverse transcriptase.
53
Zidovudine/Azidothymidine, used synergistically with lamivudine
NRTI. Thymidine analogue. Phosphorylated by host cell enzymes to triphosphate form. Inhibits HIV reverse transcriptase. Lacks 3'-OH so if incorporated, they terminate chain elongation. Lamivudine is a cytosine analogue, works the same way as zidovudine: lacks 3'-OH and inhibits HIV reverse transcriptase.
54
Hydroxyurea
Inhibits ribonucleotdie reductase. Decreases intracellular pool of pyrimidine nucleotides, potentiating effect of pyrimidine analogues.
55
Enfuvirtide
Binds to gp41, prevents the conformation change needed to complete viral fusion to host cell.
56
Saquinavir, ritonavir
Inhibits HIV protease, which is needed to cleave gag-pol polyprotein (made by ribosomal frameshift), and to cleave capsid proteins into mature forms, a step that is necessary for HIV to become infectious (P.102 BOD).
57
Interferons
IFN-α-2a used for hepatitis B, Kaposi sarcomas. | IFN-α-2b used for hepatitis C.
58
Melphalan/L-phenylalanine mustard
Nitrogen mustard alkylating agent. Treats treat chronic myeloid leukaemia and melanomas.
59
Cyclophosphamide
Nitrogen mustard alkylating agent. Converted to aldophosphamide then to phosphoramide mustard by CYP enzymes. Alkylating guanine results in inter- or intrastrand crosslinks, preventing DNA replication. If the second side chain reacts with H2O instead of a guanine, a monoalkylated guanine is produced, which can base pair with thymine. Hence there's a G-C to A-T base pair change. Also strand scission may occur when DNA repair systems try to repair alkylated DNA. Has greatest effect on B and T cells. Can cause bladder cancer via the metabolite acrolein, and other side effects via reactions with other nucleophilic groups in DNA, RNA, protein. Treats autoimmune conditions and cancer.
60
Lomustine, carmustine, semustine
Nitrosourea alkylating agent. Alkylates guanine causes interstrand crosslinks, preventing DNA replication. Can also carbamoylate proteins. Lomustine can cross BBB and treat brain cancers.
61
Cisplatin
Forms intrastrand crosslinks between two neighbouring guanines (pGpG: 65%), pApG (22%), 13% other stuff, NEVER pGpA. Causes bending of DNA duplex towards major groove, inhibits DNA replication.
62
Mitoxantrone
Anthracycline analogue that doesn't have a hydroquinone moiety (so not cardiotoxic).
63
Methotrexate
Inhibits mammalian DHFR, and competes with folic acid for active transport into mammalian cells.
64
Leucovorin
Can be converted into 5,10-CH2-FH4 without DHFR action, so has can salvage normal tissues from folate depletion. Due to the difference in FH4 requirement between normal cells and rapidly proliferating tumour cells, leucovorin reduces the toxicity of methotrexate in normal cells only.
65
5-fluorouracil
Pyrimidine analogue. Inhibits thymidylate synthetase, which uses 5,10-methylene-FH4 to form dTMP. 5-FU activity is enhanced in the presence of a lot of 5,10-CH2-FH4, so 5-FU is used synergistically with leucovorin.
66
Etoposide, amsacrine, anthracyclines
Mammalian type II topoisomerase inhibitors.
67
Camptothecins, topotecan, irinotecan
Mammalian type I topoisomerase inhibitors.
68
Vinblastine, vincristine, colchicine, podophyllotoxin (Vinka alkaloid family)
Tubulin dimers are arranged head-to-tail in linear protofilaments. Thirteen of these protofilaments together form a hollow structure, the microtubule, with a “minus” end which is usually anchored in an organising centre, and a “plus” end at which growth or shrinkage of the microtubule takes place. Vinka alkaloids bind to free tubulin dimers and prevent microtubule assembly.
69
Taxol/Paclitaxel
Causes excessive microtubule assembly. Used in drug-eluting stents.
70
Tamoxifen
Prodrug metabolised by CYP2D6 to afimoxifene and endoxifen. Oestrogen receptor antagonist. Used for breast cancer. Can exert oestrogen agonist effects in bone and uterus (can cause endometrial cancer).
71
Toremifene
Tamoxifen analogue without oestrogen agonist properties.
72
Anastrazole
Aromatase inhibitor. Used in post-menopausal women's breast cancer to prevent oestrogen formation from androgen precursors in muscle and fat.
73
Goseraline
GnRH analogue. Causes a biochemical castration due to constant stimulation of GnRH receptor in the anterior pituitary (only pulsatile GnRH release will stimulate LH and FSH secretion). Used for breast and prostate cancer.
74
Flutamide
Androgen receptor antagonist. Treats prostate cancer.
75
Prednisone
Corticosteroid prodrug converted in liver to prednisolone. Inhibits growth of lymphocytes in leukaemias.
76
Trastuzumab
Anti-HER2 monoclonal antibody. Used for breast cancer.
77
Bevacizumab
Anti-VEGF monoclonal antibody. Used with 5-fluorouracil to treat colorectal cancer, and used for NSCLC + breast cancer.
78
Cetuximab
Anti-EGFR monoclonal antibody. Treats colorectal cancer patients that are resistant to irinotecan.
79
Erlotinib, gefitinib
Inhibits dimerisation of EGFR and its ability to act as a tyrosine kinase. Treats NSCLC and pancreatic cancer.
80
Imatinib mesylate
Inhibits BCR-ABL, so treats CML. Also inhibit tyrosine kinase activity of c-kit, which is overexpressed in GIST tumours.
81
Toceranib, mastinib
Treats mastocytomas in dogs and c-kit mutations in humans.
82
Closantel
Anthelmintic. Uncouples oxidative phosphorylation. Preferential accumulation in helminths that ingest blood as closantel binds plasma proteins.
83
Clorsulon
Anthelmintic. Inhibits phosphoglycerate kinase and mutase. Preferential accumulation in helminths that ingest blood as clorsulon binds plasma proteins.
84
Mebendazole, albendazole
Anthelmintic. Cause tubulin depolymerisation
85
Levamisole
Anthelmintic. Cause NMJ depolarising blockade like succinylcholine.
86
Paraherquamide
Anthelmintic. Non-depolarising NMJ blockers like D-tubocurarine.
87
Sodium stibogluconate
Treats Leishmaniasis.
88
Isoniazid
Inhibits mycolic acid synthesis in Mycoplasma. Decreases Mycoplasma's intrinsic resistance to antibacterial agents. On the other hand, other bacteria with no mycolic acid layer have intrinsic resistance against isoniazid.
89
β-lactamase
Class A, C, D: They work the same way as peptidoglycan transpeptidase; they form acyl-enzyme intermediate with β-lactams. Instead of slow hydrolysis, making the penicinollyl-O-transpeptidase life time very long, penicinollyl-O-lactamase life time is in the milisecond range as lactamase activity involves hydrolysis of the β-lactam ring. ``` Class B: Use Zn2+ to activate a H2O molecule, catalyse its direction addition to the β-lactam ring, hydrolysing it. Hence class B lactamase can't be inhibited by Class A, C, D lactamase inhibitors. ```
90
CTX-M
ESBLs (Extended spectrum β-lactamases). Arose from plasmid transfer or point mutations in existing β-lactamases. Can hydrolyse extended-spectrum cephalosporins.
91
Aminoglycoside resistant bacteria
Aminoglycosides use specific OH and NH2 groups to bind to 16S rRNA of 30S subunit. These bacteria modify those groups to prevent binding in 3 ways: (1) N-acetylation of NH2 group by acetyl-CoA. (2) O-phosphorylyl transfer of γ-phosphate group of ATP to OH group. (3) O-adenylyl transfer of α-phosphate group of ATP, resulting in transfer of AMP moiety to OH group.
92
Methicillin
Has a bulky-2,6-dimethoxybenzoyl substituent which enhanced the lifetime of the methicillyol-O-lactamase acyl enzyme intermediate, effectively inactivating the β-lactamase. In 1950: methicillin is used against gram-positives that are resistant to penicillin.
93
MRSA
Continued β-lactam use selected for MRSA. Has the mecA gene which encodes a new β-lactam-insensitive bifunctional transglycosylase/transpeptidase called penicillin-binding protein 2A. Has fem gene whose products adds a pentaglycine crossbridge to PG strand before crosslinking; this modified PG strand is a better substrate for the new transpeptidase generated by mecA gene.
94
Vancomycin resistant bacteria
Increasing use of vancomycin to treat gram positive MRSA infections selected for drug-resistant enterococci. D-Ala-D-Ala terminal changed to D-Ala-D-Lactate due to 5 genes, encoded on 2 operons. Vancomycin sensed by VanS. VanS phosphorylates VanR. VanR induces expression of VanH/VanA/VanX operon. VanH is lactate dehydrogenase, which turns pyruvate into lactate. VanX is D-Ala-D-Ala peptidase. VanA/B is D-Ala-D-Lactate synthetase. VanA/B same mechanism but VanA's product is resistant to both vancomycin and teicoplanin (a vancomycin analogue), whilst VanB's product is only resistant to vancomycin. D-Ala-D-Lactate forms one less H-bond with vancomycin, causing a 1000-fold decrease in vancomycin's binding affinity. Some bacteria have VanC which is D-Ala-D-Ser synthetase. This only causes a 10-fold decrease in binding affinity.
95
Macrolide resistance
70% of MRSA also resistant to macrolides due to methylation of a specific adenine (A2058) in the 23S rRNA in the 50S ribosomal subunit by RNA N-methyltransferases, which is close to the macrolide binding site. A2058 methylation also affects lincosamide and streptogramin B binding. Ketolides, a third generation form of macrolides, are less likely to be effected.
96
Multidrug resistance
Needed for resistance to hydrophobic drugs that can enter via non-protein mediated diffusion. One efflux pump system gives resistance to many drugs due to the broad specificity. Gram negatives also have accessory protein that span the periplasm and an outer membrane porin. (1) Streptococcus pneumoniae has PatAB: ATP-dependent multidrug transporter. (2) AcrAB-TolC in E.coli. (3) MexAB-OprM in Pseudomonas aeruginosa.
97
Multiple drug resistance
``` Simultaneous expression of MULTIPLE antibiotic resistance mechanisms, each specific for a drug or class of drugs. Can arise from the use of a regulon, controlling resistance genes located on a resistance plasmid called R-factor. ```
98
Drug resistance in cancer cells
(1) Detoxified by CYP enzymes or glutathione conjugation. (2) Altered target: Modified topoisomerases resistant to etoposide. (3) Increase in DNA repair pathways: Nitrosourea resistant cells can repair alkylated guanine using alkyltransferases. (4) Metabolic bypass: Methotrexate resistance due to enhanced expression of DHFR, mutations in the folate carrier, which reduces affinity for methotrexate. (5) Drug efflux pumps: P-glycoprotein/MDR1, ABCG2 (breast cancer resistance protein).
99
Clavulanate
β-lactamase inhibitor - acts as a suicide subsrate for the lactamase.
100
Co-amoxiclav/Augmentin
Clavulanate + Amoxicillin
101
Unasyn
Sulbactam (penicillin analogue) + ampicillin
102
Oritavancin
Vancomycin analogue with hydrophobic biphenyl substituent which increases activity on vancomycin-resistant enterococci by 100-fold.
103
Ramoplanin
Targets lipid pentapeptide intermediates formed during cell wall synthesis. Resistance less likely as gene mutations can only affect lipid structure indirectly through alterations in enzymes make the lipid.
104
Teixobactin
Binds lipid II. Resistance less likely as gene mutations can only affect lipid structure indirectly through alterations in enzymes make the lipid.
105
Ivermectin
Increases opening of glutamate gated chloride channel at NMJ. Increased chloride causes paralysis.
106
Praziquantal
Increases permeability to calcium, depolarising blockade, paralysis.

MODA (6 decks)

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