Antibiotic_Cell Wall and Mycobacterium Flashcards by Grace Lee

Broad Spectrum Antibiotics

Drugs that work against both classes of bacteria.

How well did you know this?

Not at all

Perfectly

Extended Spectrum Antibiotic

Drug whose selectivity is broadened by chemical modification.

How well did you know this?

Not at all

Perfectly

Gm- outer membrane characteristics. (2)

1) Relatively impervious
2) Transport of drugs through TRANSMEMBRANE PORES
a. favor small hydrophilic drugs

How well did you know this?

Not at all

Perfectly

What two drugs are too big to be effective against Gm- bacteria?

Vancomycin and Daptomycin

- cannot pass through Gm- transmembrane pores

How well did you know this?

Not at all

Perfectly

Molecular make up of the Peptidoglycan layer. (2)

1) Polysaccharide chain made up of
- N-acetyl-glucosamine (NAG)
- N-acetylmuramic acid (NAM)
2) Five peptide units hanging off of Polysaccharide chain
- Last two peptides are usually D-Ala - D-Ala

How well did you know this?

Not at all

Perfectly

Enzyme that joins the sugars of the polysaccharide chain.

Transglycosylase

How well did you know this?

Not at all

Perfectly

Enzyme that joins the sugar-linked peptides to x-linked polysaccharide chains.

Transpeptidase/Penicilin Binding Protein (PBP)/Ser-Enzyme

How well did you know this?

Not at all

Perfectly

Penicillin mimics what two AA of the peptide bridge precursor?

D-Ala-D-Ala

How well did you know this?

Not at all

Perfectly

Core structure of primary Beta-lactam antibiotics

Beta-lactam ring

How well did you know this?

Not at all

Perfectly

Mechanism: Synthesis of peptidoglycan x-link. (2)

1) Transpeptidase (Ser-Enzyme) binds D-Ala-D-Ala —> D-Ala-Ser-Enzyme + D-Ala (the last D-Ala got kicked out)
2) Glycine comes in forming a peptidoglycan x-link
a. Ser-enzyme is recycled

How well did you know this?

Not at all

Perfectly

Mechanism: B-lactam antibiotic action.

Penicillin binds Transpeptidase (PBP/Ser-Enzyme)

 - Ser-Enzyme is NOT recycled
 - Bacteria can no longer form Peptidoglycan x-links

How well did you know this?

Not at all

Perfectly

Characteristic: B-lactam antibiotic. (3)

1) Irreversible Rxn
2) Effective against GROWING bacteria
3) Bacteriocidal (during peptidoglycan production)
- without peptidoglycan wall, cells burst due to osmotic pressure

How well did you know this?

Not at all

Perfectly

Mechanism and Result: B-lactamase action (3)

Hydrolysis of B-lactam ring

1) Serine B-lactamase binds penicillin
2) Forms a complex that allows H2O to hydrolyze B-lactam ring of penicilin
3) A hydrolyzed B-lactam can no longer bind PBP
- Has no therapeutic effect

How well did you know this?

Not at all

Perfectly

Genomic characteristics: B-lactamase (2)

Encoded in both chromosomal genes and plasmids

1) Chromosomal B-lactamase genes show INDUCIBLE expression
- Genes are either amplified or expression was upregulated due to environmental changes
2) Plasmid B-lactamase genes are typically expressed constitutively
- Can be transferred from one organism to another
- Responsible for spread of resistance

The genetic origins of B-lactamases will determine whether or not it is effected by B-lactamase inhibitors such as Clavulanic acid.

How well did you know this?

Not at all

Perfectly

1) Many Cell Wall drugs work selectively against ___
2) Fewer Cell Wall drugs work selectively against ___
Choices: (Gm+ or Gm-)

1) Gm+

2) Gm-

How well did you know this?

Not at all

Perfectly

Clavulanic acid - Most active against:

Detail not important for exam

PLASMID encoded B-lactamases

Staphylococci
Salmonella
Shigella
H. influenza
N. gonorrhoae
E. coli
K. pneumoniae

How well did you know this?

Not at all

Perfectly

Calvulanic acid - Least effective against:

Chromosomally encoded B-lactamases

Pseudomonas
Enterobacter
Serratia
Citrobacter

How well did you know this?

Not at all

Perfectly

Characteristic: B-lactamase inhibitor. (2)

Clavulanic acid

1) By itself has NO antibacterial activity
- ONLY effective if combined with other B-lactam antibiotics
2) Bind B-lactamases covalently and inactivate irreversibly

How well did you know this?

Not at all

Perfectly

Characteristics: Common Penicilin

Penicillin G

1) Acid labile
2) B-lacatamase susceptible
3) Suitable for Gm+, Gm- cocci

How well did you know this?

Not at all

Perfectly

Characteristics: Anti-staphlococcal penicillins

Cloxacillin

1) Acid STABLE
2) B-lacatamase resistant
3) NOT suitable for:
- enterococci
- anaerobic bacteria
- Gm- cocci
- Gm- rods

How well did you know this?

Not at all

Perfectly

Characteristics: Extended-spectrum penicillins

Amoxicillin

1) Acid STABLE
2) Inactivated by lactamases
3) Greater activity against Gm-
- highly effective in penetrating the outer membrane

How well did you know this?

Not at all

Perfectly

Uses of Amoxicillin (4)

Not emphasized in lecture

1) Sinusitis
2) Otitis
3) UTI
4) Lower respiratory tract infections

How well did you know this?

Not at all

Perfectly

Adverse reactions: Penicillin (2)

1) Superinfection with other microbes
- Oppotunistic microbes such as candidiasis can invade post antibiotic therapy

2) Allergic Reaction
- All penicillins are cross reacting, hence past claims of reactivity are frequently unreliable.

Generally non-toxic at grams/day dose

How well did you know this?

Not at all

Perfectly

Substitution for patients allergic to Penicillin

Cephalosporin (2nd generation or higher)

How well did you know this?

Not at all

Perfectly

Resistance: Penicillin (3)

1) Upregulation of chromosomally encoded B-lactamases 2) Acquisation of B-lactamases by horizontal gene transfer from other bacteria 3) Mutation of the primary PBP

Cephalosporin Generations (4)

1st: Cefazollin 2nd: Cefamandole 3rd: Ceftazidime 4th: Cefepime

Cephalosporin: 1) Broad spectrum but better for Gm+ 2) Restricted to surgical prophylaxis 3) Does NOT penetrate CNS

Cefazolin (1st generation Cephalosporin)

Cephalosporin: 1) Extended coverage of Gm- 2) No allergic cross-reactivity with penicillin

Cefamandole (2nd Generation Cephalosporin)

Cephalosporin: 1) Extended gm- activity at the expense of Gm+ 2) Effective against inducible B-lactamase but not against constitutive B-lactamase 3) Some cross blood brain barrier

Ceftazidime (3rd generation Cephalosporin)

Cephalosporin: 1) More resistant to chromosomal B-lactamases 2) True broad spectrum drugs (Both Gm+ and Gm-) 3) Penetrate CNS 4) Appropriate for MRSA

Cefepime (4th generation Cephalosporin)

Beta lactam cell wall synthesis inhibitors (4)

1) Penicillin 2) Cephalosporin 3) Monobactams 4) Carbapenems

Newest Cephalosporin approved for use against MRSA.

Ceftaroline

Characteristics: Monobactams (5)

1) Relatively resistant to B-lactamases 2) Active against Gm- rods 3) NO activity toward Gm+ - does not bind transpeptidases of Gm+ or anaerobic bacteria 4) NO cross reactivity with penicillin 5) Given IV

Adverse effects: Monobactams

No major toxicities. Occasional skin rashs

Characteristic: Carbapenems (5)

1) Broad Spectrum 2) There may be CROSS-SENSITIVITY in patients with penicillin allergies 3) Penetrate CNS 4) All cleared renally 5) Given IV 6) Resistant against serine B-lactamases but not metallo B-lactamases

Given with some carbapenems to inhibit renal dehydropeptidases. (Increase half life of carbapenems)

Cilastatin

Carbapenem drug resistant to modification by renal dehydropeptidases

Meropenem

Monobactam drugs

Aztreonam

Carbapenem drugs (2)

1) Imipenem | 2) Meropenem

Adverse effects: Carbapenems (2)

1) Nausea, vomiting, diarrhea, skin rashes. | 2) Seizures may occur in patients with renal insufficiency

Non-B-lactam cell wall synthesis inhibitors

1) Vancomycin

1) Glycopeptide 2) Active against Gm+, esp. staphlyococci 3) Bactericidal for actively growing cellls 4) Binds the cell wall rather than enzymes used to make it 5) Enter CNS

Vancomycin (IV)

Antibiotics: Glycopeptides

1) Vancomycin 2) Oritavancin 3) Dalbavancin

Mechanism: Vancomycin (2)

1) Drug binds tightly to D-Ala-D-Ala | 2) Binding interferes with BOTH transglycosylation and transpeptidation reactions

Resistance: Vancomycin

1) Switch in the peptidoglycan pentapeptide from D-Ala-D-Ala to D-Ala-D-Lac (Lactic acid) - Leads to a loss of hydrogen bond that decreases affinity of drug to pentapeptide by 1000 fold

Adverse effects: Vancomycin (3)

Minor: 1) phlebitis at injection site 2) chills, fever 3) rare ototoxicity and nephrotoxicity

Important Drug Combination: Vancomycin

Often given with aminoglycosides or gentamicin for treatment of enterococcal infections

Alternative drugs to Vancomycin due to Vancomycin's long term IV use. (7-10 days of IV injection at hospital required for treatment) (2)

1) Dalbavancin - Administered in two injections. - First injection - Day one - Second injection - Day eight 2) Oritavancin - Only need ONE IV dosing

Antibiotics: Lipopeptides (2)

1) Daptomycin (Pore former) | 2) Polymyxin (Membrane disrupter)

Antibiotic: 1) Forms pores in membrane that allow K+ loss without cell rupture 2) There is NO release of toxins 3) Approved for Gm+ skin and soft tissue infections that involve MRSA 4) 7-14 days by IV

Daptomycin (Lipopeptide)

Antibiotics: 1) Bind outer membrane of Gm- leading to permeability of both inner and outer membranes 2) Commonly used topically in form of triple antibiotic (neosporin)

Polymyxins (Lipopeptide)

Antibiotic: | Inhibit MurA - preventing conversion of NAG to NAM

Fosfomycin

Characteristics: Fosfomycin Resistance: Utility: Pregnancy usage:

``` Resistance - Loss of drug transport into cell - MurA of TB is naturally resistant Utility - Active against Gm+ and Gm- - Used for uncomplicated UTIs Pregnancy - Oral administration only ```

Antibiotic: | Inhibit lipid phosphatase that dephosphorylates lipid carrier of peptioglycan subunits

Bacitracin Peptidoglycan mechanism: 1) NAM-NAG-pentapetide complex is assembled inside the cell 2) Complex attaches to a phopholipid facing the inside of the cell 3) In order for the phopholipid to attach to the NAM-NAG complex, it must first get dephosphorylated 4) Bacitracin inhibits the dephosphorylation of the phospholipid preventing it from attaching to the NAM-NAG complex

Characteristics: Bacitracin (3)

1) ONLY active against Gm + 2) Only used topically because of nephrotoxicity 3) Usually used in combination with other antibiotics

Antibiotic: | Competitive inhibitor of Alanine racemase and D-Alanine ligase

D-Cycloserine D-Ala-D-Ala synthesis 1) L-Ala inside the bacterial cytosol is converted to D-Ala by Alanine Racemase 2) Two D-Ala are put together by D-alanine ligase

Characteristics: D-cycloserine

1) Structurally related to D-alanine 2) Drug is reserved for TB treatment - Second line drug with serious side effects: - Dose related CNS toxicity

Drugs that target Mycolic Acid. (3)

1) INH 2) ETA 3) PAS

1st line prodrugs for TB: Activation by bacteria is required. (2)

1) PZA --> POA (Pyrazinoic Acid) | 2) INH --> INH-NAD

1) Targets large beta subunit of RNA Polymerase - inhibiting elongation 2) Effective against slow growing INTRACELLULAR Mtb

Rifampin (RIF)

Target Mycolic acid

Isoniazid (INH)

Inhibits protein synthesis in DORMANT bacteria

Pyrazinamide (PZA)

1) Target Arabinogalactan | 2) Effective against fast growing EXTRACELLULAR Mtb

Ethambutol (EMB)

Bacterial enzyme that activates prodrug INH --> INH-NAD

KatG (Catalase Peroxidase)

Target of INH-NAD

Fab1 (InhA) of FAS-II | - Prevent elongation of Mycolic acid

Vitamin responsible for adverse effects of INH

Pyridoxine (B6)

What mechanism effects INH metabolism

Acetylation

Effect of Rifampin on excreted body fluids.

Turns urine, sweat, and tears purple and red. | Benign

Advantages of Rifabutin and Rifapentine over Rifampin (RIF) (4)

1) Longer half life 2) More Potent 3) Better membrane permeability - enter macrophages easier 4) Decreased induction of CYP3A - allows better compatibilty with other medications

POA mechanism

1) Inhibit RpsA from binding tmRNA | 2) Inhibit Trans-Translation

Adverse Effects: EMB

Red-Green color blindness and Optic Neuritis | - Hence, NOT prescribed to children

Antibiotic_Cell Wall and Mycobacterium Flashcards

(71 cards)