Unit 2 Flashcards
Streptomycin spectrum:
aerobic Gram- bacteria
Streptomycin toxicity:
ototoxic and nephrotoxic
Aminoglycoside central structure:
2-Deoxystreptoamine
Streptidine for Streptomycin
Aminoglycoside mechanism of action:
Transport:
- Alter outer membrane to pass through.
- Actively transported by 02-dependent transport.
Cellular target:
- Bind 16S rRNSA of 30S irreversibly.
- Misreads the mRNA: improper folding.
- Inhibit initiation of protein synthesis.
- Polysomes dissociate into non-functional monosomes.
Gentamycin Family includes (SIGN):
G - Gentamicin (mixture of 3 compounds)
S - Sisomicin
N - Netilmicin
I - Isepamicin
Kanamycin Family includes:
Kanamycin (mixture of 3 compounds)
Amikacin
Tobramycin
Neomycin Family includes:
Neomycin (neomycin B and C, and neamine)
Paromomycin
Aminoglycoside Class includes what families?
Streptomycin
Gentamycin
Kanamycin
Neomycin
Aminoglycoside Resistance (4-types):
Three forms:
Decrease in drug uptake, or Accumulation.
- Altered porin channels
- Active efflux
- Altered ability to cross cytoplasmic membrane
Alter Ribosomal Structure.
- Altered protein or rRNA decreases acces/binding affinity.
Aminoglycoside Modifying Enzymes (AMEs)
- Group transerases that modify OH or NH2 groups:
Types of AMEs:
Aminoglycoside O-Phosphotransferases (APH)
- adds Pi
Aminoglycoside O-Nucleotidyltransferases (ANT)
- adds nucleotide
Aminoglycoside N-Acetyltranserases (AAC)
- adds acetyl group
Bifunctional AMEs - most important:
- AAC(6')-APH(2'')
- adds acetyl and Pi groups.Tetracyclines spectrum:
Both gram+ and gram- bacteria
Tetracycline absorption depends on:
di- and trivalent metal ions
usually Mg2+
Caution with dairy and calcium supps.
Tetracyclines movement with Mg2+
Tc-M enter porin.
Tc and M dissociate in periplasmic space.
Tc passes the cytoplasmic membrane alone.
Tc joins M in cytosol.
TC-M attack ribosome.
Tetracycline mechanism of action:
Bind 16S rRNA of 30S.
Block binding of aminoacyl-tRNA reversibly.
Prevents elongation of peptide chain.
May be bad to use with penicillins - wall can’t be destroyed if it isn’t being built.
Types of Tetracyclines:
Chlortetracycline. Tetracycline. Doxycycline. Minocycline. Tigecycline.
Tetracycline Resistance (4-types):
Enzymatic inactivation. Target modification. Energy-dependent efflux mechanism. Ribosomal protection proteins - Tet(O) and Tet(M) - act like EF-Tu and EF-G elongation factors. - GTPases needed for protein synthesis - mech: dissociate tetracyclines from ribosome - revive the ribosomes function.
Macrolides spectrum of activity:
Similar to penicillins; gram+
Macrolide mechanism of action:
Bind 50S subunit reversibly.
Inhibit protein synthesis.
Usually bacteriostatic.
*Same for Lincosamides.
Macrolides include:
Erythromycin A and salts/ester-prodrugs: - Erythromycin Stearate - Erythromycin Ethyl Succinate - Erythromycin Estolate Second Generation Macrolides: - Azithromycin: "azalide" - Clarithromycin - Telithromycin: "Ketolide"
Macrolide Resistance:
Intrinsic: Gram- impermeability of outer membrane to hydrophobic macrolides.
Acquired Resistance, 3:
1 - Target modification; methylation of 23S rRNA
-MLS
-*M=Marolides, L=Lincosamides, S=StreptograminB
2 - Drug Inactivation
- Erythromycin Esterases I and II: open to linear chain.
-Macrolide 2’-Phosphotransferase
3 - Active efflux
Lincosamides include:
Clindamycin
Lincomycin
Lincosamides spectrum:
Gram+ and some anaerobes.
Effective for staph in bones and joints (my knee this summer!)
Lincosamide mechanism of action:
Bind 50S subunit reversibly.
Inhibit protein synthesis.
Usually bacteriostatic.
*Same for Macrolides.
Oxazolidinones include:
Linezolid
Tedizolid (newer)
Oxazolidinone Mechanism of Action:
Overall: Disrupt protein biosynthesis - bacteriostatic.
Specifically: Bind 23S rRNA of 50S subunit - at site near 30S subunit; blocks the formation of 70S.
Oxazolidinone SAR:
3’-fluorine: activity
Oxazolidinone ring: intact
Chloramphenicol
New class of antibiotic Broad Spectrum Inhibit 50S - peptide formation - near macrolide/clindamycin site: not in conjunction. Good CNS access - meningitis Grey Baby Syndrome - Pancytopenia - low blood cells Resistance: Chloramphenicol Acetyltransferase (CAT)
Retapamulin used for:
Topical treatment of Impetigo.
Retapamulin MOA:
Acts on 50S subunit:
Unique binding involving L3 of P-site.
Inhibits peptidyl transer, blocking P-site interactions, and therefore preventing formation of active 50S.
Retapamulin Resistance:
Mutation in L3 protein.
Efflux.
Fidaxomicin used for:
Clostridium difficile.
*Little to no effect on normal fecal flora.
Fewer CDI recurrences.
Not absorbed.
Fidaxomicin MOA
Inhibits “sigma-dependent” transcription of bacterial RNA polymerase.
Bactericidal.
Fluoroquinolones inhibit:
Nucleic acid metabolism and function.
DNA Gyrase
Relaxes supercoiled DNA.
- relieves torsional strain during replication.
- the only enzyme that can also supercoil DNA.
DNA Topoisomerase IV
A decatenating enzyme:
- resolves interlinking daughter chromosomes following DNA replication.
Fluoroquinolone/Quinolone MOA:
Bind Gyrase-DNA complex
Nalidixic Acid
First Generation Fluoroquinolone.
Rirst Quinolone - prototype of the rest.
Strong acid - pKa of 1.
Extensively metabolized to 7-OH-Methyl-nalidixate
Nonfluorinated and resistance to it is wide spread, so today it is limited to uncomplicated UTI’s
- usually due to Gram- bacteria.
Norfloxacin
Second Generation Fluoroquinolone.
C-6 F-group.
100x more potent than nalidixic acid.
Broader Gram- and some Gram+
Ciprofloxacin
Second Generation Fluoroquinolone.
Top 200
More potent than Norfloxacin
Better absorption - distribute to bone/soft tissues.
Safe, but: Q/T prolongation, photosensitivity.
With penicillin for Anthrax.
Ofloxacin and Levofloxacin
Second Generation Fluoroquinolones. Top 200 S+R = Oflaxacin, S only = Levofloxacin High CSF - Meningitis. Q/T prolongation. Active against MDR-TB - second line treatment.
Sparfloxacin
Third Generation Fluoroquinolone.
Two F-groups.
Q/T prolongation and photosensitivity.
Gatifloxacin
Third Generation Fluoroquinolone.
Topical eye drop.
Sever blood glucose fluctuations - insulin secretion.
Moxifloxacin
Fourth Generation Fluoroquinolone.
Top 200.
“Respiratory quinolone” - pneumonia and TB.
long t1/2.
Gemifloxacin
Fourth Generation Fluoroquinolone.
Pneumonia or bronchitis
Recently, skin infections
- something about women under 40, and skin rashes, and hormone therapy.
Fluoroquinolone Resistance:
Mutate Gyrase and topo IV genes.
- gyrA gene for Gyrase: chromosomal.
Decrease intracellular accumulation of drug.
recG gene - repair fluoroquinolone damage.
Plasmid resistances
- Qnr proteins interfere with binding.
- Fluoroquinolone Modifying Enzymes; mutated AAC
- Efflux pumps
Fluoroquinolone Toxicity/Side Effects:
*Tendon Rupture Q/T prolongation Photoxicity Peripheral neuropathy Skin lesions, blisters, second degree burns, vasodisturbances.
Sulfonamides in general:
Antifolates
Sulfonamide MOA:
Inhibit folic acid biosynthesis needed for:
- synthesis of thymidine and purines.
- synthesis of several amino acids.
Specifically: inhibit DHPS -or- serve as DHPS substrate.
- mimic PABA
- ends pathway.
Selective toxicity: mammals do not synthesize folate; target-DHPS is not present.
Also, bacteria cannot take in our folate to make up for it.
Protonsil
Prototype Sulfonamide antibiotic
In cells - converted to Sulfanilamide.
pKa = 10; crystallizes in kidney
Hypoglycemic inducing property lead to development of sulfonylurea diabetic drugs.
Trisulfa Pyrimidine
Sulfadiazine, Sulfamerazine, and Sulfamethazine.
Equal parts to total 500mg dose.
Reduced crystallization problem.
Sulfisoxazole
Sulfonamide Antibiotic.
pKa = 5
Bitter taste.
Sulfamethoxazole
Sulfonamide Antibiotic.
Used with Trimethoprim
- achieve 20:1 ratio with 20:4 dose
- Trimethoprim inhibits DHFR; way more so for bacterial DHFR than mammalian.
Sulfacetamide
Sulfonamide Antibiotic.
Topical use only
acne and eye infection
Mupirocin
Miscellaneous
Top 200.
External use - Impetigo.
Blocks synthesis of isoleucyl-tRNA.
Metronidazole
Miscellaneous
Top 200.
For C. diff
NO2 moiety forms radical (like Nitrofurantoin)
Discolors urine reddish-brown
With alcohol - Disulfiram-like effects; very sick.
MOA: 1-electron transfer to form radical using ferredoxin.
Nitrofurantoin
Miscellaneous Top 200 Broad spectrum, not ps. For UTIs NO2 moiety forms radical (like Metronidazole) Discolors urine yellow-brown.
Mycobacterium TB
Why difficult? - complex outer wall; mycolic acid. - divide very slowly. - mostly dormant. Treatment times: - typically 6 months - MDR for 2 years - Extensive Drug Resistant for 2 years in hospital. Patients with HIV: 1/3 will die.
Isoniazid (INH)
Anti-TB antibiotic.
Perfect: selective, cheap, oral, low toxicity.
MOA: inhibit mycolic acid biosynthesis.
Specifically: Targets inhA (Enoyl-Acyl Carrier Protein Reductase) involved in mycolic acid synthesis.
INH oxidized by KatG; releases active metabolite.
Metabolite reacts with NADH-cofactor of inhA
Resistance: mutation of inhA.
Rifampin
Anti-TB antibiotic.
First-Line treatment
MIC = 5ng/mL, but is selective under 5ug/mL - it’s very safe.
MOA: Inhibits DNA-dependent-RNA-Polymerase - binds to it’s P-site.
Works better in conjunction with cell wall inhibitors - Ethambutol.
- Strong CYP-inducer:
- bad for HIV patients on CYP sensitive drugs.
Can cause harmless discoloration of body fluids.
Rifabutin
Anti-TB antibiotic.
Less CYP inducing than Rifampin - different side chain
Better for HIV patients on CYP sensitive drugs.
Rifapentine
Anti-TB antibiotic.
Long t1/2.
Rifaximin
Not for TB
Less than 1% absorbed; used for GI infections.
Ethambutol (EMB)
Anti-TB antibiotic
Synergistic with Rifampin.
MOA: EMB inhibits the cell wall biosynthesis of actively dividing cells by inhibiting Arabinosyltransferase.
Also, EMB may interfere with the transfer of arabinose to the cell wall acceptor.
- This causes an accumulation of the lipid carrier called decaprenyl phosphoarabinose.
May cause a decreases in visual acuity.
Pyrazinamide (PZA)
Anti-TB antibiotic
PZA is able to target dormant/semidormant bacteria within the macrophages they reside.
- Key component needed to shorten therapy to 6 months.
Prodrug - needs to be hydrolyzed by Pyranizamidase.
MOA: PZA Inhibits trans-translation (the destruction of improperly folded proteins).
- Binds to RpsA: ribosomal protein S1.
PZA-resistant strains have mutated Pyranizamidase
- pnCA gene.
May cause some mild hyperuricemia.
Second Line Treatment for TB
Aninoglycosides Ethionamine Cycloserine Aminosalicylin Capreomycin Fluoroquinolones
Streptomycin
Sort of Aminoglycoside.
Streptidine ring.
Gram- aerobes and TB.
Ototoxic and Nephrotoxic.
Gentamicin
AG antibiotic - Gentamicin Family. Three compound mixture. Parenteral for serious gram- Topical for ps. Physically incompatible with B-lactams.
Kanamycin
AG antibiotic - Kanamycin Family
Three compound mixture; mostly A.
Ototoxic
Used for MDR-TB.
Amikacin
AG antibiotic - Kanamycin Family Derivative of Kanamycin Added AHBA group. Half as potent Much less prone to AG modifying enzymes.
Tobramycin
AG antibiotic - Kanamycin Family
Derivative of Kanamycin
3’-DeoxykanamycinB
For Ps., not TB
Often used with B-lactams (not physically)
Active towards Gentamicin resistant strains.
Neomycin
AG antibiotic - Neomycin Family.
Topically only b/c of Nephrotoxicity severity.
Paromomycin
AG antibiotic - Neomycin Family.
Used for Dysentery.
Tetracycline
Tetracycline Antibiotic
No chlorine - better oral bioavailability and duration than Chlortetracycline.
Doxycycline
Tetracycline Antibiotic Top 200 No Chlorine C-6 hydroxyl group - improved activity. STIs - gonorrhea and syphillis Lime disease, malarial prevention. Not with dairy or Calcium supps - reduce absorption; superinfections.
Minocycline
Tetracycline Antibiotic Top 200 Additional di-methy-amine group No C-6 hydroxy Better absorption, longer t1/2
Tigecycline
Tetracycline Antibiotic Most recent. Only injectable. "protected glycine side chain" - 9-tert-butyl-glycylamido group. Less convenient but active against tetracycline resistant strains.
A2058 Ribosomal Residue
Bacteria - A: can be methylated as a form of resistance.
Mammals - G: extra methyl group provides steric protection from Macrolide antibiotics.
Erythromycin A
First Generation Macrolide
Prototype.
Acid sensitive, bitter taste.
Erythromycin Ethyl Succinate
First Generation Macrolide
Better absorption
Most common oral form of Erythromycin.
Will be hydrolyzed by our esterases.
Erythromycin Estolate
First Generation Macrolide
Propionate ester form as an acid salt with laurel sulfate.
Increased absorption and decreased bitter taste.
Clarithromycin
Second Generation Macrolide Top 200 C-6 hydroxymethyl group - protects from acid. Better absorption than first gen. Better activity for Gram- and Gram+ *Used for MAC *Q/T prolongation *Hepatotoxic
Azithromycin
Second Generation Macrolide
Top 200
Oxime intermediate leads to addition of Hydroxylamine and then rearrangement reaction; N pulled down into skeleton; 15 membered ring.
“Azalide” - Acid stable, Better activity, long t1/2
Gonorrhea
Lincomycin
Lincosamide Antibiotic
Very active against Gram+ and some anaerobes
Staph in bones and joints.
Clindamycin
Lincosamide Antibiotic Chlorinated version Usually IV, but also oral for C. diff - superinfection possible - use with vancomycin, metronidazole, or fidaxomicin
Linezolid
Oxazolidinone Antibiotic First of class Good for Gram+, MRSA, and VRE strains. Side Effects bad: - Myelosuppression - Acts as MOAI reversibly; depression
Tedizolid
Oxazolidinone Antibiotic
Newer
Longer t1/2 - reduced dose
