10/11 - Cell Wall Inhibitors Flashcards
Gram Positive Bacteria
- *THICK & UNSTRUCTURED**
- *Thick Layer of Peptidoglycan**
Wall Teichoic Acids = WTA
&
LipoTeichoic Acids = LTA
Gram-Negative Bacteria
- *THIN & NEAT**
- *LipopolySaccharide = LPS**
PeriPlasmic Space = Space between CM & LPS
Cytoplasmic Membrane = CM
LIPID 2
Building Block of PeptidoGlycan
Lipid 2 is:
synthesized in cell cytoplasm
transported across the:
inner membrane
attached to the:
growing peptidoglycan polymer
What does the
CROSSLINKING between Glycan Strands?
PeptidoGlycan Architectuer
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
What is this?
B-Lactam Group
PHARAMACORE of ALL B-LACTAM AB’s
Penicillin
Cephalosporins
Carbapenems
Monobactams
Mechanism of Action
of B-Lactam ABs
- *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
What AB?
+ Activity
Penicillin G
B-Lactam ring fused to a THIAZOLIDINE RING
GRAM POS
Acid & Akali -Labile
Sensitive to action of INACTIVATING PENICILLINASES
How was this Penicillin Improvement made?
Better ACID STABILITY
EWG SIDE CHAINS –> ↓rate of acide hydrolysis
Amoxicillin + Cloxacillin = More acid-Stabile
Can better withstand acidic pH of the stomach & taken orally
What is 6-APA?
- *Semi-Synthetic Precursor** for
- *NEWER PENICILLINS**
Cleave of BENZYL MOIETY of Penicillin G
Various penicillins maindy differ by the:
N6 side chain = R
How was this Penicillin Improvement made?
BROADER SPECTRUM?
- *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*
How was this Penicillin Improvement made?
Resistance to Beta-Lactamases
- *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
Beta Lactamase Inhibitors
Function
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
Mechanism of Resistance
B-Lactams
- *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
What Antibiotic?
CEPHALOSPORINS
activity is modulated by two areas:
R2 @C7 and R1 @C3
Started from
7-ACA or converted from Penicillins
What Generation of Cephalosporin?
&
Special Activity?
1st Generation Cephalosporins
Cephalothin-Cafazolin-Cephelexin
Gram-POS Cocci** & **Streptococci
What Generation of Cephalosporin?
&
Special Activity?
- *2nd Generation Cephalosporins**
- *Cefamandole Nofate - Cephaclor**
Improved activity against some:
- *GRAM NEGATIVES**
- *H.Influenzae**
What Generation of Cephalosporin?
&
Special Activity?
3rd Generation Cephalosporins
Cefotaxime - Cefixime
X = 3
- *Better activity** for:
- *Gram NEG**
- but reduced activity for:*
- *Gram Pos**
What Generation of Cephalosporin?
&
Special Activity?
- *4th Generation Cephalosporins**
- *Cefepime**
similar to 3rd gen X’s
Active against:
Pseudomonas Aeruginosa
What Generation of Cephalosporin?
&
Special Activity?
5th Generation Cephalosporins
Ceftaroline Fosamil (Teflaro)
F=Five
Active against:
MRSA** & **VRSA
+ other Gram-Pos Pathogens
Moxalactam
Function?
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
What Drug?
- *CARBAPENEMS**
- *ThienaMycin** + Imipenem
Combines the chemical features of:
Penicillins & Cephalosporins
BOTH
Gram Pos & Neg
Carbapenem
MoA
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
- *Newer Carbapenems**
- *IMIPENEM + CILASTATIN**
What Improvements?
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
Newer Carbapenems
Meropenem + Ertapenem + Doripenem
INCREASED STABILITY
but they are:
- *ACID-LABILE_ –> _only IV ADMIN**
- also VERY EXPENSIVE*
What Drug?
& Uses?
- *MONOBACTAM**
- *AZTREONAM**
Narrow-Spectrum AB
VVV
Aerobic Gram-Negative Bacteria
&
PCN ALLERGY PATIENTS
Fosfomycin
Uses / Target
Cell-Wall inhibitor of the NON-B-Lactam Type
Uncomplicated UTIs
active against:
Carbapenem-Resistant KLEBsiella Pneumoniae
Bacitracin
Target / Use
Cell-Wall Inhibitor of the NON-B-Lactam Type
Interferes with the:
Dephosphorylation of Lipid carrier
TOPICAL ONLY
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
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
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**
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*
Nalidixic Acid
- *QUINOLONE**
- *Topoisomerase Inhibitor**
Helped us find the target of:
DNA GYRASE
Active against:
BOTH Gram POS&NEG
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
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
Basis of SELECTIVITY of
Quinolone AB’s
Bacterial Type 2 TopoIsomerases
are
Structurally different from Eukaryotic Cells
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
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
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
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
DAPTOMYCIN
Class / Uses
CATIONIC CYCLIC LIPOPEPTIDE
Daptomycin = Cubicin, requires CALCIUM ION for activity
Effective for:
- *Gram-Pos Cocci**
- *MRSA & MSSA** & VRE
DaptoMycin
Cationic Cyclic Lipopeptide
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
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
Polymyxins
Use / Class
Cationic Cyclic Lipopeptide
BACTERICIDAL
Used for:
Multidrug-resistant GRAM-NEG Bacteria
Pseudomonas Aeruginosa & Acinetobacter baumanii
LAST LINE
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**
Bacterial Resistance to
POLYMYXINS
Cationic Cyclic Lipopeptide
- *Gram -NEG-** pathogens can:
- *LPS MODIFICATIONS**
- -> REDUCING their NEG charge on surface
less interaction with DRUG + LPS
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**
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
- *Azithromycin**
- *Bacteriostatic vs BacterioCIDAL?**
BacterioSTATIC** for **GRAM POS
&
BacterioCIDAL** for **Gram -NEG-
Pseudomonas Aeruginosa
(strept Pneumoniae)
WHAT ANTIBIOTICS MAY PROMOTE
HOSPITAL AQUIRED C.DIFF INXN
loss of gut bacterial diversity & AB resistance:
CEPHALOSPORINS
CLINDAMYCIN
FLUOROQUINOLONES
