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

10/11 - Cell Wall Inhibitors Flashcards

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?

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?

A
  • *CARBAPENEMS**
  • *ThienaMycin** + Imipenem

Combines the chemical features of:
Penicillins & Cephalosporins

BOTH
Gram Pos & Neg

22
Q

Carbapenem

MoA

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?

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

A

INCREASED STABILITY

but they are:

  • *ACID-LABILE_ –> _only IV ADMIN**
  • also VERY EXPENSIVE*
25
Q

What Drug?

& Uses?

A
  • *MONOBACTAM**
  • *AZTREONAM**

Narrow-Spectrum AB
VVV
Aerobic Gram-Negative Bacteria

&

PCN ALLERGY PATIENTS

26
Q

Fosfomycin

Uses / Target

A

Cell-Wall inhibitor of the NON-B-Lactam Type

Uncomplicated UTIs

active against:
Carbapenem-Resistant KLEBsiella Pneumoniae

27
Q

Bacitracin

Target / Use

A

Cell-Wall Inhibitor of the NON-B-Lactam Type

Interferes with the:
Dephosphorylation of Lipid carrier

TOPICAL ONLY

28
Q

Vancomycin

Use / Target

A

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
Q

Televancin

Target / use

A

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
Q

Resistance to VANCOMYCIN

A
  • *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
Q

Dalbavancin & Oritavancin

A

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
Q

Nalidixic Acid

A
  • *QUINOLONE**
  • *Topoisomerase Inhibitor**

Helped us find the target of:
DNA GYRASE

Active against:
BOTH Gram POS&NEG

33
Q

Quinolones

Target & MoA

for GRAM NEGATIVE

A

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
Q

Quinolones

Target & MoA

for GRAM POSITIVE

A
  • *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
Q

Basis of SELECTIVITY of
Quinolone AB’s

A

Bacterial Type 2 TopoIsomerases
are
Structurally different from Eukaryotic Cells

36
Q

Norfloxacin** / **Levofloxacin** / **Ciprofloxacin

Class / Improvements?

A
  • *FLUOROQUINOLONES**
  • *2nd gen Quinolone**

More POTENT & Broader Spectrum

Used for:

  • *STDs** / Lower Respiratory Tract & skin Infxns
  • *Systemic Infxns**

Anthrax - Cipro & levofloxacin

37
Q

Mechanisms of Resistance

QUINOLONES

A

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
Q

Moxifloxacin

Class / Improvements

A

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
Q

NovoBiocin

Target / Use

A
  • *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
Q

DAPTOMYCIN

Class / Uses

A

CATIONIC CYCLIC LIPOPEPTIDE
Daptomycin = Cubicin, requires CALCIUM ION for activity

Effective for:

  • *Gram-Pos Cocci**
  • *MRSA & MSSA** & VRE
41
Q

DaptoMycin
Cationic Cyclic Lipopeptide

MoA & Target

A

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
Q

DaptoMycin

Mechanisms of Resistance

A

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
Q

Polymyxins

Use / Class

A

Cationic Cyclic Lipopeptide

BACTERICIDAL

Used for:
Multidrug-resistant GRAM-NEG Bacteria
Pseudomonas Aeruginosa & Acinetobacter baumanii
LAST LINE

44
Q

PolyMyxin

MoA

A

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
Q

Bacterial Resistance to
POLYMYXINS
Cationic Cyclic Lipopeptide

A
  • *Gram -NEG-** pathogens can:
  • *LPS MODIFICATIONS**
  • -> REDUCING their NEG charge on surface

less interaction with DRUG + LPS

46
Q

LL-37 (a-helix): cathelicidin
&
HNP-1 (b-sheet): a-defensin

A
  • *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
Q

How do IV antibiotics still reach our GUT?

and cause:
Alteration of GUT MICROBIOTA?

A

BILIARY EXCRETION

12% of Pen G IV dose –> excreted to bile

11-65% of Ceftriaxone IV dose –> excreted to bile

48
Q
  • *Azithromycin**
  • *Bacteriostatic vs BacterioCIDAL?**
A

BacterioSTATIC** for **GRAM POS

&

BacterioCIDAL** for **Gram -NEG-
Pseudomonas Aeruginosa

(strept Pneumoniae)

49
Q

WHAT ANTIBIOTICS MAY PROMOTE

HOSPITAL AQUIRED C.DIFF INXN

A

loss of gut bacterial diversity & AB resistance:

CEPHALOSPORINS

CLINDAMYCIN

FLUOROQUINOLONES

PDAT6 ID (31 decks)

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