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PDAT6 ID > 6/7 - AB's of the Ribosomes > Flashcards

6/7 - AB's of the Ribosomes Flashcards

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1
Q

Small Ribosomal Subunit
FUNCTION
&
AB targtts

A

SELECTION of aminoacyl-tRNA according to mRNA codons

Antibiotics will:
interfere with tRNA binding
or
interfere with the accuracy of protein synthesis

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2
Q

Large Ribosomal Subunit
FUNCTION
&
AB targtts

A

Polymerization of AA’s -> Poly Peptides

Antibiotics will:
inhibit peptide-bond formation
or
inhibit Growth of the nascent peptide chain

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3
Q

Why is the ribosome evolutionary preferred antibiotic target?

A

Bacterial rRNA genes are REDUNDANT

several identical genes in genomes of bacteria code for rRNA

MOST CONSERVED

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4
Q

Antibiotic Size in comparison to Ribosome

A

AB’s are 5000x SMALLER than ribosomes

AB’s inhibit translation by interacting with the:
FUNCTIONAL CENTERS of the ribosome

Drugs target the:
Ribosomal RNA

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5
Q

Why does
Targeting ABs -> the RIBOSOME delays the appearance of resistance traits?

A

A single spontaneous resistance mutation that occurs in one rRNA gene
DOES NOT CONFER SUFFICIENT LEVEL OF RESISTANCE
because:
majority of the ribosome will STILL carry on unmutated rRNA

23k+ macrolide resistant strains –> only 0.3% developed resistance

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6
Q

What Antibiotic?

A

MACROLIDE

  • *Large Compound –>** can only hit GRAM POS
  • too large to get across gram neg*

Macrolactone + 2 Sugars

Erythromycin is unstable @low pH –> converts to inactive ketal

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7
Q

What Antibiotic?

A

2nd Gen Macrolide

AZITHROMYCIN

Prevent formation of the inactive ketal
(erythromycin, unstable @ low pH)

Better ACID stability & Broader Spectrum

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8
Q

How were MACROLIDES IMPROVED?

2rd Generation

-MYCINS

A

2nd Gen = Clarithro / Azithro / Roxi
Better:
Acid Stability & Broader Spectrum
things to prevent formation of the inactive ketal (erythromycin)

LOWER MIC

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9
Q

How were MACROLIDES IMPROVED?

3rd Generation KETOLIDES

-MYCINS

A

3rd Gen = KETOLIDES (Telithromycin)

KETO GROUP –> clandinose sugar
=better activity againstRESISTANT STRAINS

CARBAMATE GROUP
= improves PK & PD

EXTENDED SIDE CHAIN
improves binding to robosome

drawbacks = liver toxicity

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10
Q

Macrolide (-mycin)

MoA

A

Macrolides bind to the:

  • *Large Ribosomal Subunit** @ Nascent peptide Tunnel
  • *PARTIALLY OBSTRUCT the EXIT TUNNEL**

Protein-Specific Inhibitors​
allow for synthesis of other proteins, DOES NOT ABOLISH ALL
depends on the sequence, some proteins can still be made

  • *Alkyl-Aryl Side chain of KETOLIDES**
  • -> additional contacts w/ ribosome = ↑drug affinity
  • *Desosamine –> A2058**
  • target of resistance mechanisms*
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11
Q

Mechanisms of Resistance:

Macrolides
(-mycins)

A

CHEMICAL MODIFICATION of rRNA
DiMethylation of A2058 (desosamine contact) @ 23S rRNA catalyzed by:
rRNA methyltransferase ERM
INDUCIBLE & activated only in the presence of Macrolide AB’s

  • *Ribosome Protection**
  • *MsrE –> REMOVES AB from ribosomal tunnel**

Ribosome Modification
rRNA mod // mutations in rRNA & ribosomal protein genes = VERY RARE

  • *Drug Efflux**
  • *MeF** Macrolide-specific pumps // multi-drug Pumps
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12
Q

What does MsrE do?

To WHAT Antibiotic?

A

Resistance mechanism for
MACROLIDES & STREPTOGRAMIN B

  • *RIBOSOME PROTECTION** For Macrolides:
  • *EJECTS AB from RIBOSOMAL TUNNEL**
  • *Msr Transporters: Drug Efflux** for
  • *Both macrolides & streptogramin B**
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13
Q

What is the MAJOR Mechanism of RESISTANCE for

MACROLIDE AB’s?
(-mycins)

A

Chemical Modification of rRNA

Di-methylation of A2058 (desosamine target) in the 23S rRNA
catalyzed by:
rRNA methyltransferase ERM

ERM = inducible gene & activated only in presence of Macrolides

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14
Q

Macrolide (-mycin)

Clinical Uses

A

GRAM POSITIVES

Oral agents for:
Upper & Lower Respiratory Tract Infections

urethritis / skin infections

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15
Q

Which Drug?

A

OXAZALIDINONES
Linezolid / Tedizolid

complicated skin infxns = MRSA

GRAM POS
mostly + drug resistant S.Areus

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16
Q

Oxazolidinones
linezolid / tedizolid

MoA

A

Binds to the:

  • *Large Ribosomal** subunit in the
  • *Catalytic PEPTIDYL TRANSFERASE Center**

Linezolid clashes with the placement of aminoacyl-tRNA
& prevents polymerization of AA’s into proteins

inhibits the ELONGATION STEP of translation
specifically peptide bond formation when:
ALANINE is present @ penultimate position of nascent protein
alanine = very common, needed for ALL PROTEINS in bacteria

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17
Q

Major ADR of
Oxazolidinones

& Why?

(​linezolid / tedizolid)

A

Structure of ribosomal site where Oxazolidonones bind in bacterial ribosome is:
nearly the SAME in human MITOCHONDRIAL RIBOSOMES
allows linezolid to:
inhibit MITO translation in human cells

Reversible Myelosupression
from prolonged treatment

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18
Q

Mechanism of Resistance for:
Oxazolidinones

(​linezolid / tedizolid)

A

RIBOSOMAL MODIFICATION

Mutations in rRNA & ribosomal protein genes = RARE
↑mutated rRNA genes = ↑resistance

+

ACQUIRED rRNA modification
binding of the AB overlaps with the binding site of natural AB’s
aquired CFR gene encoding rRNA methyltransferase
C8 Methylation @ A2503

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19
Q

What is the CFR gene?
often present on transposons & plasmids (facilitates its spread)
&
What AB does it affect?

A

RIBOSOMAL MODIFICATION** = **Acquired rRNA Modification
Mechanism of Resistance

C8 Methylation @ A2503
CFR gene has overlapping sites in peptidyl transferase center with other naturally occuring AB’s (chlorophenicol)

OXAZOLIDINONES** + **PLEUROMUTILINS

LINCOSAMIDES** + **STREPTOGRAMINS A
+ 16 member ring macrolides

ALL LARGE RIBOSOME TARGETS
except for Streptogramins B + certain macrolides

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20
Q

What Antibiotic?

A

LINCOSAMIDES

Oral / IV / Topical

ANAEROBIC GRAM POS
+
effect on GUT MICROBIOME –> C.DIFF RISK

(Lincomycin + Clindamycin)

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21
Q

LINCOSAMIDES

(Lincomycin + Clindamycin)

MoA

A

Binds to:
Large Ribosomal Subunit** on the **Peptidyl Transferase Center

Clashes w/ AminoAcyl tRNA
VV
Inhibits formation of PEPTIDE BONDS

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22
Q

Mechanisms of Resistance

LINCOSAMIDES
(Lincomycin + Clindamycin)

A

Ribosome Modification
ERM METHYLTRANSFERASE (also for macrolides & streptogramin B)
by dimethylating A2058 = MLSb Resistance
MONOMETHYLATION by some ERM confers resistance to specifically Lincosamides

  • *Drug Modification**
  • *LNU ENZUMES** –> inactivate clindamycin by adenylation
  • *Drug Efflux**
  • *LSA(B)** & LSA(A) & VGA (A,C,E)
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23
Q 
**What does ERM do?**
and to:
what antibiotic(s)?
Study These Flashcards
A

Mechanism of Resistance (rRNA Mutations & Modifcation) for:
MACROLIDES + LINCOSAMIDES + STREPTOGRAMIN B
by:
Dimethylating A2058 = MLSb Resistance

monomethylation is sufficient for LINCOSAMIDES

24
Q

What Antibiotic?

Study These Flashcards
A

STREPTOGRAMINS
(A) DalfoPristin + (B) QuinuPristin

Synercid = 30% A + 70% B
Improved solubility –> INJECTABLE

IV ONLY
for life-threatening infxns caused by vanco-resistant Enterococcus faecium & complicated skin infxn by staphylococci

  • *GRAM POSITIVE**
  • *MRSA + MSSA**
25
* *_STREPTOGRAMIN B_** * *(B) Quinupristin** ## Footnote **BINDING SITE & MoA**
**QuinuPristin** binds in the: **_EXIT TUNNEL_** & ***_PREVENTS the EGRESS of newly made protein_***
26
* *_STREPTOGRAMIN A_** * *(A) DalfoPristin** ## Footnote **BINDING SITE & MoA**
**Dalfopristin** binds in the: **_Peptidyl Transferase Center_** & ***_Inhibits AA polymerization_***
27
**_STREPTOGRAMINS_** (A) DalfoPristin + (B) QuinuPristin **MoA**
**_SYNERGISTICALLY_** = **BACTERICIDAL** & active @***lower concentrations*** **Dalfopristin REMODELS the rRNA structure** (targets the peptidyl transferase center) VV **Stimulating BINDING of QuinuPristin** (targets the EXIT tunnel)
28
**_STREPTOGRAMINS_** (A) DalfoPristin + (B) QuinuPristin ## Footnote **Mechanisms of Resistance**
* *_Drug Modification_** * *VAT AcetylTransferase** --\> ***inactivates Dalfopristin*** * *Vgb Lyase** --\> **opens the central circle** of **quinupristin** * *_Ribosome Modification_** * *ERM methyltransferase** --\> dimethylation of A2058 * *_Drug Efflux_** * *VG**_A_** & LS**_A_**** = **streptogrammin _A_** * *MSR** = **macrolides & streptogramin B**
29
What is: **VAT AcetylTransferase** what does it do and to what?
Mechanism of Resistance = **Drug Modification** **_*INACTIVATES***_ & _***MODIFIES*_** **_DALFOPRISTIN_** Streptogramin A
30
What is: **VGB LYASE** and what does it do to what?
Mechanism of Resistance = **Drug Modification** **Opens the CENTRAL CIRCLE** component of: **_QUINUPRISTIN_** Streptogrammin B
31
**What drug classes act on the LARGE RIBOSOMAL SUBUNIT?**
**_MACROLIDES_** Erythromycin -\> Clarithro/Azithro/Roxithro -\> Telithro/Solithro **_OXAZOLIDINONES_** Linezolid / Tedizolid **_LINCOSAMIDES_** Lincomycin / Clindamycin **_STREPTOGRAMINS_** (A) Dalfopristin + (B) QuinuPristin = Syncercid 30-70 **_PLEUROMUTILINS_** PleuroMutilin / RetapaMulin / LefaMulin
32
**What Antibiotic?**
**_PLEUROMUTILINS_** PleuroMutilin + RetapaMulin + LefaMulin **_Complex DITERPENE Structure_** **TOPICAL** for **Skin infections = Impetigo / Wounds / Lacerations** **_Gram-Positive Pathogens_**
33
**_PLEUROMUTILINS_** PleuroMutilin + RetapaMulin + LefaMulin ## Footnote **Binding Site & MoA**
Bind to the: * *_Peptidyl Transferase Center**_ in the _**Large Ribosomal Subunit_** * interferes w/ placement of tRNA substrates* bind only the the **EMPTY RIBOSOME** specifically ***_inhibit the INITIATION of TRANSLATION_*** *can NOT bind to ribosome w/ nascent chain*
34
**Mechanisms of Resistance** **_PLEUROMUTILINS_** PleuroMutilin + RetapaMulin + LefaMulin
* *_Ribosome Modification_** * *CFR** --\> **rRNA methylation** **@A2503** * also Lincosamides / oxazolidinones / streptogramin A / macrolides* **_Drug Efflux_** **VgaC** & **VgaE** confer resistance to **Streptogramins & Lincosamides as well _LsaA_** = intrinsic resistance to just pleuromutilins
35
What do **VgaC** & **VgaE** do? and to what AB's?
**_EFFLUX PUMPS_** mechanisms of **resistance for:** **_Streptogramins**_ + _**Lincosamides**_ + _**Pleuromutilins_**
36
**What Antibiotic?**
**_4,6 - Substituted AMINOGLYCOSIDE_** Kanamycin / Gentamicin / Tobramycin / Plazomicin **TB** / **Plague / Endocarditis** **_Aerobic GRAM-NEG_** MycoBacteria ***_Usually in combo with Beta-Lactams_***
37
**What Antibiotic?**
* *_4,5 - Substituted AMINOGLYCOSIDE_** * *Neomycin** / **Paromycin** **TB** / **Plague / Endocarditis** **_Aerobic GRAM-NEG_** MycoBacteria ***_Usually in combo with Beta-Lactams_***
38
**_AMINOGLYCOSIDES_** Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin ## Footnote **Site of Action**
Act on: * *_Small Ribosomal Subunit_** * flexibility of AG's allow their* ***adaptation to shape of binding pocket*** Binding --\> **induces conformation of _DECODING CENTER_**
39
**_AMINOGLYCOSIDES_** Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin ## Footnote **MoA**
**_MISCODING_: Synthesis of Erroneous Proteins** the ribisome accepts **INCORRECT aminoacyl-tRNA** *incorporates a WRONG AA in the growing protein* **_SELF-PROMOTED UPTAKE_** disrupts membrane structure --\> **increased AG permeability** **_BACTERICIDAL_**
40
**_AMINOGLYCOSIDES_** Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin ## Footnote **Mechanism for SELECTIVITY**
* *Nucleotide 1408** of the **Small Subunit** is: * *_A in BACTERIA_** * but **B in Eukaryotes*** ## Footnote **Adenine @ this position is REQUIRED for TIGHT binding of AG's**
41
**_AMINOGLYCOSIDES_** Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin **Side Effects** & **WHY?**
**_NEPHRO**_ & _**OTOTOXICITY_** due to action on the: **_Mitochondrial Ribosomes_** the key nucleotide for **AG binding is A (like bacteria****)**, *not G* *AG's can bind and inhibit translation* **Familial mutations** in deconding center of mito ribosomes can **predispose patients to OTOTOXIC effects of AG's**
42
**_AMINOGLYCOSIDES_** Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin ## Footnote **Mechanisms of Resistance**
**_Drug Modification_** specific functional **side groups** in AG could be: **_N-Acetylated**_ / _**O-phosphorylated**_ / _**O-adenylated_** steric prevention **overcome by eminination of the group targeted by _resistance enzymes_** * *_Ribosome Modification_** * *ArmA**/**RmtA** --\> **_methylates G1405_** in the AG binding site * *NpmA** --\> **_modifies A1408_**
43
**What AB?**
**_STREPTOMYCIN_** AminoGlycoside interacts with the ribosome at a **site CLOSE but *DIFFERENT*** from other AG's Pharmacore = **STREPTAMINE** **Highly _BASIC guanidino_ groups** facilitates interactions with **rRNA**
44
**What AntiBiotic?**
**_TETRACYCLINES_** 2nd Gen = Doxycycline + Minocycline ## Footnote **BOTH Gram-Pos & Gram-Neg** **lyme disease + CAP Syphilis**
45
**What Antibiotic?**
* *3rd Gen Tetracycline = _GLYCYLCYCLINES_** * *TigeCycline + Eravacycline** * *IV DRUGS** Indicated for: **Skin/Ab Infxns** + **_Community Acquired Pneumonia_** Bind in conventional tetracycline site in **small ribosome**, BUT are: able to **_withstand the major tetracycline RESISTANCE mechanisms_**
46
**How do Tetracyclines** have **GRAM-NEG activity?**
* *_POLAR NATURE_** * *Basic + Acidic Groups** allow for it to get through the: **PORIN CHANNELS** of the outer membrane of Gram-Neg Bacteria **Gram-Pos = Diffusion**
47
**What is CRITICAL for Tetracycline Activity?**
**_STEREO-ORIENTATION_** of the **DimethylAmino-Moitety** **Epimerization** --\> ***_reduces activity of TetraCyclines_*** **_Ring A_** can undergo **enolization & re-protonization** ***4-epitetracycline = inactive***
48
**_TETRACYCLINE_** ## Footnote **MoA**
Tetracycline acts on the: **_Small Ribosome_** and **_Blocks binding of AminoAcyl-tRNA_** * *Tigecycline TAIL** --\> forms **additional interactions** * *20x affinity** vs tetracycline
49
**_TETRACYCLINE_** **Mechanisms of Resistance**
**_RIBOSOME PROTECTION_** primarily in **_Gram-POS_** bacteria **_TetM**_ + _**TetO_** = proteins that **"CLEAN" the ribosome** = **Evict Tetracycline** **_DRUG EFFLUX_** primarily in **_GRAM-NEG_** bacteria **Transmembrane Efflux Pumps** active in **1st/2nd generation** *not for Glycylcyclines like tigecycline*
50
**What Antibiotic?**
**_RIFAMPICIN_** **Potent + Broad-Spectrum AB** used in: **Anti-TB combination therapy** RED COLOR **_BacteriCIDAL_**
51
**_RIFAMPICIN_** **Target?**
**_RNA POLYMERASE_** Rifampicin binds in the: **Nascent RNA chain EXIT tunnel** of the **_Beta-Subunit_** of RNA poly *similar to MACROLIDES --\> exit tunnel = BUT CLOGS COMPLETELY* VV **_INHIBITION of INITIATION of TRANSCRIPTION_** *inhibits formation of 2nd or 3rd PHOS bonds*
52
**Mechanisms of Resistance** **_RIFAMPICIN_**
**_Mutations in GENE ENCODING_** on the **beta-subunit** of **RNA polymerase**
53
**What Antibiotic?**
**_SULFONAMIDE_** **Synthetic BacterioSTATIC AB's** that mimic / structural analogs of **PABA** an intermediate of the **FOLATE biosynthesis Pathway**
54
**_Sulfonamide_** Sulfamethazole ## Footnote **Target / MoA**
Sunfonamides **mimic & compete** with: **_PABA_** which inhibits the activity of: **_DIHYDROPTEROATE SYNTHASE_** Which ultimately inhibits the synthesis of: * *TetrahydroFolate** * precursor of NUCLEOTIDES & AA's*
55
**Improvements in SULFONAMIDES**
**Sulfisoxazole** / **Sulfamethoxazole** **_EWG_** @ the **AMIDE GROUP** ↑**Potency** by ***_reducing pKA of Amino group_*** VV brings it **closer to the pKA of PABA** Mods also: ↑**Drug Solubility** @ neutral pH by helping it **avoid crystalization of sulfonamides in Kidneys**
56
**What Drug?**
**_TRIMETHOPRIM_** Target is * *Sufficiently DIFFERENT in bacterial pathogen** & **human host** * *_DiHydroFolate Reductase_** *Sulfonamide's target is ONLY in the BACTERIAL PATHOGEN DiHydropteroate Synthase not in Human Cells*
57
**_Trimethoprim_** **Target / MoA**
**_DIHYDROFOLATE REDUCTASE_** *another enzyme in Folate Synthesis* found in BOTH HUMANS & Bacteria, but greater affinity for bacteria **BACTRIM** **Sulfamethoxazole** + **Trimethoprim** Acts **Synergistically**

PDAT6 ID (31 decks)

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