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PDAT6 ID > 10/11 - Cell Wall Inhibitors > Flashcards

10/11 - Cell Wall Inhibitors Flashcards

(49 cards)

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1
Q

Gram Positive Bacteria

A
  • *THICK & UNSTRUCTURED**
  • *Thick Layer of Peptidoglycan**

Wall Teichoic Acids = WTA
&
LipoTeichoic Acids = LTA

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2
Q

Gram-Negative Bacteria

A
  • *THIN & NEAT**
  • *LipopolySaccharide = LPS**

PeriPlasmic Space = Space between CM & LPS

Cytoplasmic Membrane = CM

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3
Q

LIPID 2

A

Building Block of PeptidoGlycan

Lipid 2 is:
synthesized in cell cytoplasm
transported across the:
inner membrane
attached to the:
growing peptidoglycan polymer

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4
Q

What does the
CROSSLINKING between Glycan Strands?

PeptidoGlycan Architectuer

A

TRANSPEPTIDASE
TPase
hydrolyzes peptide bonds–> covalent link
B-Lactam AB’s target the reaction of the formation of the covalent intermediate

Peptidoglycan consists of polysaccharide chains that are cross-linked by peptide “BRIDGES”

Peptide Tails –> protrude from it HELICALLY = RIGIDITY of CELL WALL

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5
Q

What is this?

A

B-Lactam Group

PHARAMACORE of ALL B-LACTAM AB’s

Penicillin

Cephalosporins

Carbapenems

Monobactams

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6
Q

Mechanism of Action

of B-Lactam ABs

A
  • *C-N** Bond in B-Lactam ring is SIMILAR to:
  • *Peptide Bond connecting 2 D-alanine Residues** of the Peptidoglycan Precursor

TPase –> recognizes B-lactam as substrate
& forms a COVALENT BOND w/ the AntiBiotic

Transpeptidase** = **IRREVERSIBLY INACTIVATED

Also:
Penicillin Binding Proteins
other enzymes of cell-wall biosynthesis that are targeted by B-Lactams

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7
Q

What AB?

+ Activity

A

Penicillin G

B-Lactam ring fused to a THIAZOLIDINE RING

GRAM POS

Acid & Akali -Labile

Sensitive to action of INACTIVATING PENICILLINASES

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8
Q

How was this Penicillin Improvement made?
Better ACID STABILITY

A

EWG SIDE CHAINS –> ↓rate of acide hydrolysis

Amoxicillin + Cloxacillin = More acid-Stabile

Can better withstand acidic pH of the stomach & taken orally

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9
Q

What is 6-APA?

A
  • *Semi-Synthetic Precursor** for
  • *NEWER PENICILLINS**

Cleave of BENZYL MOIETY of Penicillin G

Various penicillins maindy differ by the:
N6 side chain = R

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10
Q

How was this Penicillin Improvement made?
BROADER SPECTRUM?

A
  • *MORE POLAR GROUPS**
  • *-NH2** or -COOH

↑Access of B-Lactams into the Periplasmic space of GRAM-NEG

Ex.
Ampicillin / Amoxacillin / Carbenicillin

Penicillins enter through the:

  • *PORINS** in the outer membrane
  • hydrophobic side chains = BENZYL group –> INTERFERE w/ passage*
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11
Q

How was this Penicillin Improvement made?
Resistance to Beta-Lactamases

A
  • *BULKY SIDE CHAINS**
  • *hinders access of B-lactamase to the AMIDE BOND**

Ex.
Methicillin + Cloxacillin

Main mechanism of resistance to PCN is:
Secretion of enzymes called B-Lactamases
which
hydroyze amide bond in the B-lactam ring

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12
Q

Beta Lactamase Inhibitors

Function

A

Resemble B-Lactam AB’s
that function by:
Binding to B-lactamase Enzymes
&
INACTIVATING the enzyme w/o being degraded

Ex.
Clavulanic Acid / Sulbactam / Tazobactam

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13
Q

Mechanism of Resistance

B-Lactams

A
  • *Beta Lactamase**
  • hydrolyze amide bond of B-lactam Ring*

Target Modification
mutations in TransPeptidases & PBPs
acquisition of the mecA gene** –> encodes resistance **PBP2’
which supports cell-wall biosynthesis even when ALL OTHER PBP’s are covalantly inactivated by the drug

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14
Q

What Antibiotic?

A

CEPHALOSPORINS
activity is modulated by two areas:
R2 @C7 and R1 @C3

Started from
7-ACA or converted from Penicillins

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15
Q

What Generation of Cephalosporin?
&
Special Activity?

A

1st Generation Cephalosporins
Cephalothin-Cafazolin-Cephelexin

Gram-POS Cocci** & **Streptococci

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16
Q

What Generation of Cephalosporin?
&
Special Activity?

A
  • *2nd Generation Cephalosporins**
  • *Cefamandole Nofate - Cephaclor**

Improved activity against some:

  • *GRAM NEGATIVES**
  • *H.Influenzae**
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17
Q

What Generation of Cephalosporin?
&
Special Activity?

A

3rd Generation Cephalosporins
Cefotaxime - Cefixime
X = 3

  • *Better activity** for:
  • *Gram NEG**
  • but reduced activity for:*
  • *Gram Pos**
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18
Q

What Generation of Cephalosporin?
&
Special Activity?

A
  • *4th Generation Cephalosporins**
  • *Cefepime**

similar to 3rd gen X’s

Active against:
Pseudomonas Aeruginosa

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19
Q

What Generation of Cephalosporin?
&
Special Activity?

A

5th Generation Cephalosporins
Ceftaroline Fosamil (Teflaro)
F=Five

Active against:
MRSA** & **VRSA
+ other Gram-Pos Pathogens

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20
Q

Moxalactam

Function?

Study These Flashcards
A

Cephalosporin can ALSO be inactivated by B-lactamases

BULKY SIDE CHAIN
gives greater RESISTANCE to B-lactamases

7-a-methoxy group
increases resistance even further

21
Q

What Drug?

Study These Flashcards
A
  • *CARBAPENEMS**
  • *ThienaMycin** + Imipenem

Combines the chemical features of:
Penicillins & Cephalosporins

BOTH
Gram Pos & Neg

22
Q

Carbapenem

MoA

Study These Flashcards
A

Can penetrate through PORIN holes of Gram-NEG bacteria
&
resistant to ESBL (extended spectrum B-lactamases)

Combo of:
Penicillins + Cephalosporins
but also target:
Ld Transferase = LdT
which is another enzyme of cell-wall biosynthesis

23
Q
  • *Newer Carbapenems**
  • *IMIPENEM + CILASTATIN**

What Improvements?

Study These Flashcards
A

Side Amino gorup of Thienamycin
can react with the B-lactam ring of ANOTHER THIENAMYCIN
= unstable in concentrated solutions

  • *Imipenem** = modified side chain
  • but is susceptable to hydrolysis by*: DHP-1 @ renal brush border

CILASTIN** = **DHP-1 INHIBITOR

IMIPENEM + CILASTATIN
is a combination to prevent this hydrolysis

24
Q

Newer Carbapenems
Meropenem + Ertapenem + Doripenem

Study These Flashcards
A

INCREASED STABILITY

but they are:

  • *ACID-LABILE_ –> _only IV ADMIN**
  • also VERY EXPENSIVE*
25
**What Drug?** **& Uses?**
* *_MONOBACTAM_** * *AZTREONAM** **Narrow-Spectrum AB** VVV **_Aerobic Gram-Negative Bacteria_** & **_PCN ALLERGY PATIENTS_**
26
**Fosfomycin** Uses / Target
**Cell-Wall inhibitor** of the ***_NON-B-Lactam Type_*** **Uncomplicated UTIs** active against: **_Carbapenem-Resistant KLEBsiella Pneumoniae_**
27
**_Bacitracin_** Target / Use
**Cell-Wall Inhibitor** of the **_NON-B-Lactam Type_** Interferes with the: **Dephosphorylation of Lipid carrier** **TOPICAL ONLY**
28
**Vancomycin** Use / Target
**Cell-wall Inhibitor** of the **_Non-Beta-Lactam Type_** **_GLYCOPEPTIDES_** **_Gram-POS**_ & _**BacteriCIDAL_** **_MRSA_** **&** **_Cephalosporin Resistant Organisms_** Binds tightly to the: D-Ala residues at the end of peptidoglycan precursor **Lipid 2** --\> ***inaccessible to TPase*** --\> ***no crosslinking***
29
**Televancin** Target / use
Similar to **Vancomycin** = **GLYCOPEPTIDES** but has: **Additional Hydrophobic Side Chain** + **Polar Phos Group** _DUAL ACTION_ **_Binds to Cell Membrane_** & _↑**membrane permeability**_ x10 stronger BacteriCIDAL vs Vanco
30
**Resistance to VANCOMYCIN**
* *_INDUCIBLE RESISTANCE_** * *Van Gene** is activated when cells are exposed to vanco * *VRSA strains** are **more fit than VISA** * *VISA = abnormal peptidoglycan** * *thicker wall + *less cross linked*** * *Vancomycin TRAP = SPONGE**
31
**Dalbavancin & Oritavancin**
**_NEWER GLYCOPEPTIDES_** Similar to Vancomycin but have: **Hydrophobic Side Chains** Active against: **Vancomyscin Sensitive Strains** & **do NOT induce expression of VanB Resistant Gene** * *ONCE A WEEK** * VERY EXPENSIVE*
32
**Nalidixic Acid**
* *_QUINOLONE_** * *Topoisomerase Inhibitor** Helped us find the target of: **DNA GYRASE** Active against: **BOTH Gram POS&NEG**
33
**_Quinolones_** **Target & MoA** **for _GRAM NEGATIVE_**
**_DNA GYRASE_** Dual Fxn = **Negative Supercoiling** & **Relaxes Positive Supercoiled DNA** Quinolones inhibit the function of DNA gyrase by: * *forming a TERNARY COMPLEX between**: * *DNA + GYRASE + QUinolone AB** When bound: DNA Gyrase ***_can NOT RE-SEAL the CUT_*** --\> **DNA Fragmentation** **BACTERICIDAL AB**
34
**_Quinolones_** **Target & MoA** **for _GRAM POSITIVE_**
* *_TOPOISOMERASE IV_** * Similar activity to **DNA Gyrase**...* **Introduces DS-Break in DNA** In order to change the **DNA topology** **Segragation of bacterial chromosomes after completion of DNA replication**
35
**Basis of SELECTIVITY of Quinolone AB's**
**Bacterial Type 2 TopoIsomerases** are **Structurally different from Eukaryotic Cells**
36
**_Norfloxacin**_ / _**Levofloxacin**_ / _**Ciprofloxacin_** Class / Improvements?
* *_FLUOROQUINOLONES_** * *2nd gen Quinolone** **More POTENT** & **Broader Spectrum** Used for: * *STDs** / **Lower Respiratory Tract & skin Infxns** * *Systemic Infxns** **Anthrax** - Cipro & levofloxacin
37
**Mechanisms of Resistance** **QUINOLONES**
**_UPTAKE INHIBITION_** ↓**Influx** = *decreased PORIN expression* ↑**Active Efflux** = ↑**drug efflux pump** **_TARGET MODIFICATION_** Mutations in **GYRASE (-)** & **TOP 4 (+)** * *_TARGET PROTECTION_** * *Qnr (quinolone resistance) proteins --\> bind to Gyrase** **_Qunolone INACTIVATION by modifying quinolones_**
38
**Moxifloxacin** **Class / Improvements**
**_3rd Gen FLUOROQUINOLONE_** * 2nd Gen have:* * *limited activity against Gram-Pos (Strep. Pneumoniae)** & **MRSA** 3rd gen have: **Improved activity against STREPTCOCCI & STAPHYLOCOCCI & ENTEROCOCCI** & Activity against **CIPRO-RESISTANT BACTERIA**
39
**NovoBiocin** Target / Use
* *_Coumarin Containing Antibiotic_** * similar to quinolones, except they:* * **Inhibit*** **the _B-Subunit_ of DNA GYRASE** Synergistic action w/ quinolones **B-Subunit + A-Subunit** Resistance: from mutations in **B-subunit**
40
**_DAPTOMYCIN_** Class / Uses
**_CATIONIC CYCLIC LIPOPEPTIDE_** Daptomycin = Cubicin, requires **CALCIUM ION** for activity Effective for: * *Gram-Pos Cocci** * *MRSA & MSSA** & **VRE**
41
**_DaptoMycin_** Cationic Cyclic Lipopeptide ## Footnote **MoA & Target**
_Requires **CALCIUM ION** for activity_ **interacts** with **Anionic (-) cell surface (WTA/LTA)** on **Gram Pos Bacteria Walls** inserts its: * *_Hydrophobic Tail_** --\> **bacterial membrane** = **depolarize membrane** * by forming CHANNELS & leaking K+* * *Cell-Death**, *does NOT lyse like B-lactams*
42
**DaptoMycin** **Mechanisms of Resistance**
**Gram-Pos pathogens** like **S. Aureus** **_NEUTRALIZE their NEGATIVE CHARGES_** on their cell surface **WTA / LTA** is normally NEGATIVE VVV **D-Alanated WTA + LTA** & **_Lysinylated**_ _**PhosphatidylGlycerol_** *normally:* Daptomycin uses its +POS+ charge to target the -NEG- Cell wall
43
**_Polymyxins_** Use / Class
**_Cationic Cyclic Lipopeptide_** **BACTERICIDAL** Used for: **_Multidrug-resistant GRAM-NEG Bacteria_** Pseudomonas Aeruginosa & Acinetobacter baumanii **LAST LINE**
44
**PolyMyxin** **MoA**
**LAST LINE _Cationic Cyclic Lipopeptide_** **Gram -NEG-** Disrupt **cell membrane** through interaction with the: **membrane phospholipids** * *INSERT --\> membrane** & **assemble into CHANNELS & PORES** * *CELL LYSIS + DEATH**
45
**Bacterial Resistance to POLYMYXINS** Cationic Cyclic Lipopeptide
* *Gram -NEG-** pathogens can: * *_LPS MODIFICATIONS_** - -\> **_*REDUCING* their NEG charge on surface_** ## Footnote *less interaction with DRUG + LPS*
46
**LL-37 (a-helix): _cathelicidin_ & HNP-1 (b-sheet): _a-defensin_**
* *_HOST-DEFENSE PEPTIDES_** * *Cationic Anti-Microbial Peptides** Part of our: **Normal Immune System** to: **Defend agasint Bacterial & Fungal Infxns** * *Resistance to Polymyxins (-)** & **Daptomycin (+)**: * *_ALSO GIVES RESISTANCE TO OUR IMMUNE SYSTEM's CATIONIC ANTIMICROBIAL PEPTIDES_**
47
**How do IV antibiotics still reach our _GUT?_** and cause: **Alteration of GUT MICROBIOTA?**
**_BILIARY EXCRETION_** 12% of Pen G IV dose --\> excreted to bile 11-65% of Ceftriaxone IV dose --\> excreted to bile
48
* *Azithromycin** * *Bacteriostatic vs BacterioCIDAL?**
**_BacterioSTATIC**_ for _**GRAM POS_** & **_BacterioCIDAL**_ for _**Gram -NEG-_** Pseudomonas Aeruginosa | (strept Pneumoniae)
49
**_WHAT ANTIBIOTICS MAY PROMOTE_** **_HOSPITAL AQUIRED C.DIFF INXN_**
*loss of gut bacterial diversity & AB resistance:* **_CEPHALOSPORINS_** **_CLINDAMYCIN_** **_FLUOROQUINOLONES_**

PDAT6 ID (31 decks)

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