3 types of Antibiotics that inhibit tRNA binding.
4 Antibiotics that inhibit peptide bond formation between amino acids 3 & 4 from mRNA translation.
Antibiotic class that inhibits translocation of tRNA complex, thus inhibiting protein synthesis.
Which antibioc inhibits protein synthesis by 85%?
What happens to the remaining transcribed protein?
- Remaining includes "mis-reading"; "faulty proteins" --> bacterium DEATH (bactericidal)
Require _____ for uptake
Do NOT enter our cells; how do we get them inside?
Toxic so regulate dosing
- They are synergistic with beta-lactams
Aminoglycosides are effective for aerobic or anaerobic bacteria?
Aerobic ONLY (they require oxygen for uptake
Aminoglycosides: Bacteristatic or Bactericidal?
Which is the only aminoglycoside to bind to only 1 ribosomal protein?
- Therefore, a mutation provides resistance
Other aminoglycosides bind multiple ribosomal proteins so resistance by drug modification (adenyl, phosphate or acetyl attachment) - often a plasmid enzyme
Aminoglycoside used to treat tuberculosis and plague.
Aminoglycoside used topically, especially in 3 in 1 ointment
2 aminoglycosides used in broad spectrum IV therapy, often with a beta-lactam antibiotic
How are gentamicin and tobramycin used?
Used for broad spectrum IV therapy, often with a beta-lactam antibiotic.
Aminoglycoside reserved for the most resistant strains
Any one of these enzymatic additions to an aminoglycoside causes resistance.
Resistance is by modifying the drug.
What assay do you use to assess the amount of intracellular bacteria?
Since it can't penetrate the cell wall, you let the bacteria interact with the cells, add gentamicin (kills extracellular bacteria), wash to remove dead extracellular bacteria, lyse cells to release intracellular bacteria, culture the release bacteria.
Mean GNATS can NOT kill anaerobes
Mean = Amin
- G: Gentamicin
- N: Neomycin
- A: Amikacin
- T: Tobramycin
- S: Streptomycin (micin/mycin end is not unique to aminoglycosides)
- NOT= Toxicities
1) Bacteriostatic or Bactericidal?
2) Inactivated by aminoglycosides
3) Administer via?
4) Was used to treat but now unavailable in the US.
- 1) BacteriStatic
- 3) Administer via IM injection
- 4) Was used to treat PPNG (penicillinase producing Neisseria gonorrhoeae)
Tetracyclines have 4 rings. What 2 things do the tetracyclines bind to?
- Top= Ribosome binding side
- Bottom= Metal binding side
What is a major metal that tetracyclines chelate? What is this metal a part of?
Chelates Zn which is a component of metalloproteinases.
What type of antibiotic also serves as a protease inhibitor?
Long acting tetracyclines?
Long acting tetracyclines are _______ and used for?
- They are broad spectrum and used to treat:
- 1) Acne and other mild anaerobes (propionebacterium)
- 2) Atypical pneumonia (Chlamydia, mycoplasma, rickettsia)
- 3) STD (Chalmydia, GC, chancroid)
- 4) Systemic Zoonotic infections (animal-derived organisms)
- 5) Cholera
What antibiotic incorporates into bone/teeth?
Who cannot take this drug?
- Tetracycline incorporates into bone and teeth.
- It is not useful for children or pregnant women
Which class of antibiotic is used to treat cholera?
There is a large resistance to all tetracyclines except ___. This is due to mal-use in treatment of _______.
- Due to mal-use in tx of Chlamydia.
Tetracycline must accumulate in the cell and interact with the ribosome so an important resistance mechanism is?
What is one uncommon mode of resistance?
All of these resistances are _____
- Efflux Resistance (via tet protein) AND
- Ribosome Protection (RPP- ribosomal protection protein): binds the 30S ribosome so tetracyclines can NOT bind the ribosome (tigecycline is the exception)
Additional resistance is conferred by an enzyme that oxidizes tetracyclin.
All of these resistances are plasma-coded.
Cell membrane protein that mediates efflux resistance of tetracyclines?
tet protein (plasma-coded)
RPP binds to ____ and prevents _____ from binding.
Ribosomal Protection Protein binds to 30S ribosome and prevents tetracyclines from binding
Tigecycline: Extended Spectrum Tetracycline
Has the same structure as tetracyclines plus an additional chemical attachment.
Tigecycline treats ?
It is administered via?
- Some Gram-N bacteria, E.coli (NOT Pseudomonas)
- Administered via injection
- Still has teeth and bone problems
Is Tigecycline susceptible to ribosome protection and efflux resistance like the other tetracycline?
No, it overcomes these mechanisms (which are originally derived from Streptomyces)
1) Binds to what part of the ribosome?
2) Static or Cidal?
Very seldomly given today
- 1) 50S
- 2) Static, but cidal for agent of meningitis (used for meningitis in Penicillin-allergic patient)
What drug has lethal anemia as an adverse effect?
It enters mitochondria and messes-up mitochondrial metabolism, especially in cells responsible for producing RBCs.
What drug can be used for meningitis treatment in a penicillin-allergic patient?
Chloramphenicol Resistance involves what enzyme?
What does this enzyme do?
- CAT: Chloramphenicol Acetyl Transferase
- Puts an acetyl group on the enzyme
Lincosamide effective for:
Gram-P; useful in penicillin-allergic patient
lincomycin & Clindamycin
Lincosamide effective for:
Anaerobes including Bacteroides
Leads to a problem with?
- It leads to a problem with C. dificile because it wipes out all of the Bactroides which is prevalent in the gut. (Antibiotic Associated Enterocolitis)
Clindamycin has a ____ where Lincomycin has a _____.
- Clindamycin = Cl (Chloride)
- Lincomycin = OH (Hydroxyl)
Is CA-MRSA susceptible to clindamycin?
It was, but now resistance is a problem. Rifampin is sometimes used with it now to prevent re-emergence of a resistant sub-population
5 Drugs that are common causes of Antibiotic-Associated Enterocolitis.
- Clindamycin (not as commonly used as the others, but when it is used, it creates this problem)
C. difficile Cytotoxin Assay
All cells treated with same filtrate, but with Ab to C. dificile toxins. If cells still alive, then it is C. dificile. If they're not it is C. dificile and AAE.
Bacteriocidal vs. Bacteriostatic:
- Aminoglycosides- Bacteriocidal
- Tetracyclines- Bacteriostatic
- Chloramphenicol- Bacteriostatic, except against meningitis (bacteriocidal)
- Lincosamides- Bacteriostatic
- Synercid: Cidal (static for VRE)
- Retapamulin: Static
- Linezolid: Static
- Fluoroquinolone: Cidal
- Polymyxin/Daptomycin: Cidal
- Nitrofurantoin: Static
Synercid is made of two semi-synthetic Pristinamycins. What are they?
Dalfopristin (30%) and Quinpristin (70%) (streptogramins)
Synercid is often bacteriocidal. What is the exception?
Synercid is only static for VRE
What is the problem with Synercid?
It is toxic to blood vessel on injection, use a large vein to limit toxic effects
Which drug is toxin to the vein in which it is injected?
Dalfopristin and Quinpristin both bind to the ___ subunit of the ribosome.
What do they do after that?
- Dalfopristin- blocks peptide bond formation
- Quinpristin- Releases the incomplete peptide (Quin= Quit...I'm done wit chu peptide...I'm done!)
Synercid is cidal for?
Considered ineffective for?
- Cidal= Vancomycin-resistant strains of MRSA
- Static= Enterococcus faecium (including VRE strains)
- Ineffective: Enterococus fecalis
Virginamycins, used in European agriculture, is similar to?
So resistant bacterial strains exist in animal transposons.
3 Mechanisms of Synercid Resistance
- 1) Drug Efflux reaction
- 2) Enzymes: An Acetyl transferase or lyase
- 3) Methylation of the ribosome, called the D reaction
What drug is used topically to treat impetigo (ie. Staph & Strep), even in children?
What drug is used to eliminate the Staph carrier state?
Unique portion of 50S ribosome
Retapamulin is a semi-synthetic drug of the ____ family.
Formulated in _____ (trade name is Altabax).
- Pleuromutilin family
- Formulated in petrolatum
No cross resistance seen of ribosome gene or efflux in which antibiotic?
Therefore it acts on?
Acts on Mupirocin-resistant Staph, including MrSA strains)
Main adverse of effect of Retapamulin?
Skin irritation or pain
Which drug blocks translocation?
3 Main Macrolides
Macrolides are effective on
Gram-P infection, people with penicillin allergies
Macrolides are the drug of choice for which 3 bacteria?
- Mycoplasma pneumoniae "Walking pneumonia"
Which drug is good for AFB and is also used for Helicobator?
Popular drug for respiratory infections in out-patients as well as pneumonia (Haemophilus), chlamydia, and GC
Macrolides used for respiratory?
Macrolides used for Digestive
Macrolides used for STDs
Adverse effects of macrolides.
Digestive tract problems (nausea, vomiting diarrhea)
Methylase enzyme expression, to confer ribosome resistance, was only expressed in presence of erythromycin
Erythromycin diffuses across medium and causes methyllase enzyme to be expressed. This confers ribosomal resistance to clindamycin or lincomcin and causes a D shaped-are of no bacterial growth around the lyncomycin/clindamycin disc.
Now there are more strains NOT requiring induction for expression.
Linezolid binds the ___ subunit.
How does it inhibit protein synthesis?
It binds the 50S ribosomal subunit and keeps it from combining with the 30S ribosomal subunit. Therefore, the ribosome is never actually completely built.
Resistance to Linezolid is mediated by
a point mutation in the 23 S ribosomal RNA
Linezolid is active on ?
Best therapy for highly resistant Staph, pneumo, and enterococcus strain; but expensive.
Also has some uses for anaerobes and mycobacterium
Adverse effects of Linezolid (4):
- Intestinal disturbances (appetite, diarrhea, nausea)
- Tongue discoloration
- LION (linezolid induced optic neuropathy)
What causes LION?
LION= Linezolid Induced Optic Neuropathy
Caused when Linezolid reacts with mitochondrial ribosomes, especially in nerve cells
Which drug can act on mitochondrial ribosomes to cause a problem?
Antibiotics that inhibit Nucleic Acid Synthesis
- Quinolones: Inhibit topoisomerase and gyrase
- Rifampin, fidaxomicin: Inhibit RNA Pol & Sigma Factor
- Sulfa, Trimethoprim: Inhibit folic acid formation from metabolites
Which enzyme creates supercoils?
Which antibiotic inhibits that enzyme?
- DNA Gyrase
Which enzyme knicks the supercoil and makes possible for the two circles to pull apart?
Which antibiotic inhbits that enzyme?
2nd Generation Fluroquinolone
Other two are Ofloxacin and Norfloxacin
Extended Spectrum 3rd Gen. Fluroquinolone
4th Gen. Fluoroquinolones
Name the 4 prominent fluorquinolones.
The most important enzyme for Fluoroquinolones to inhibit in Gram-N bacteria is?
Gyrase (topoisomerase II)
The most important enzyme for Fluoroquinolones to inhibit in Gram-P bacteria is?
Which antibiotic is very good for Gram-N, used to work on Staph, but is not for Strep or anaerobes?
Treat UTI, bone & joint infections, etc.
Gonococcus and MRSA are often resistant now to ?
Ofloxacin vs. Levofloxacin
Ofloxacin= a standard fluoroquinolone
Mixture of two isomers. What are they?
Only one type of isomer is present. What is it?
- D-ofloxacin (weakly active) predominantes in a 5:1 mixture
- L-isomer binds well to topoisomerase and gyrase
- Less potent than ciprofloxacin
- Levofloxacin: Only has L-isomer present
- More potent, especially for Gram-P
Moxafloxacin and Gatifloxacin are more effective for Gram-P, but less effect for Gram-N than cipro
Which drug can lead to tendon damage?
You can also get excessive sun blisters
New drug designed to treat patients with antibitotic-associated enterocolitis. Works on Clostridium, but not normal flora.
Cures AND prevents re-occurences
Binds beta subunit of RNA polymerase; prevents sigma binding and enzyme action.
Rifampin, rifabutin, rifapentine
- First line drug for TB and other AFB infections
- Prophylaxis for meningitis mediated by N. meningitis
Can cause reddish-orange discoloration of urine, soft contact lenses may become discolored.
Continued therapy for TB
INH + rifampin
3-4 drug combinations of initial TB therapy
- Rifampin + INH + ...
- Pryazinamide + ethambutol (or strepto)
- Pryazinamide + Moxiflox
2 Phases of TB tx:
- Phase I: Intensive Phase = RIPE therapy
- Phase II: Continuation Phase = INH + rifampin for 4-7 months
MDR TB resists
INH & Rifamyacins
XDR TB resists
4 core drugs (INH, rifamycins, fluoroquinolone, and a second line drug (amikacin, capreomycin or kanamycin)
Inhibitors of Dihydrofloic acid Synthetase
Sulfa Drugs treat
prophylaxis of UTI
Both humans and bacteria have the enzyme dihydrofolate reductase. What drug binds to the bacteria one 40x more strongly than the human one?
PAS used uncommonly to treat
Hansen's Disease (leprosy)
Do humans and bacteria have dihydrofolate synthetase?
No, only bacteria
Synthetase inhibitors mimic?
What 3 drugs are these?
These includes Sulfa Drug, PAS, Dapsone
Sulfa drugs are usuallyused synergistically with ________ to treat ______
UTIs, CA-MRSA (sometimes w/ rifampin)
Drug combination used for empiric therapy of inflammatory diarrhea
Which drug is static in tissue and cidal in urine? Why?
Sulfa-trimethoprim is static in tissue infections because bacteria are rescued by exogenous folic acid, thymidine, or other metabolte from dying PMN or other cells. The urine does not have these and the cell dies.
Which drug can have nausea, vomiting, diarrhea, ANOREXIA, and ALLERGIC RXNS occur?
Form of sulfa drug used with trimethoprim is?
Polymyxin tail is hydrophobic or hydrophilic?
What does Polymyxin bind to? What is it effective for?
Binds to LPS, so effective for Gram-N bacteria (not Proteus)
Describe the mechanismof action of Polymyxin. Why is it toxic?
Drug disrupts cell membrane. Polymyxins don’t need cell growth, they destroy the membrane no matter what. Problem is they can’t tell the difference between bacterial membrane and our membrane. Therefore, they can be quite toxic.
What does Daptomycin bind to? What is it effective for?
Bidns to Ca2+ in th membrane of Gram-P bacteria, so useful for Gram-P bacteria
Why can Daptomycin not be used for pneumonia?
It binds to surfactants in the lung.
Daptomycin treats drug resistant strains including?
Its adverse effects include?
Effective for VRE, MRSA, and pneumococcus
Can cause muscle pain and intestinal problems
Which drug forms poisons under ANAEROBIC conditions?
Used as IV for serious anaerobic infections! (often used with Penicillin G for anaerobic brain abscess)
Good prophylactic therapy for recurrent UTIs
Resistatnt mutants are very rare, and some people take this drug for years.
What bacteria does Nitrofurantoin treat specifically? What 2 bacterial does it not treat?
Treats: E. coli, KES, Staphylococcus, and Enterococcus
Does not treat: Pseudomonas or Proteus
Mupirocin is produced by Pseudomonas, blocks protein synthesis by blocking the binding of?
Isoleucine to its tRNA
Drug used topically for a few Gram-P bacteria that is used to treat?
Impetigo caused by Staph or Strep or to eliminate Staphylococcus aureus from "Staph carriers"
Fluoroquinolones can NOT be used for?
Strep, anaerobes, gonococcus, or MRSA