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

6/7 - AB's of the Ribosomes Flashcards

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)?
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?

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
Q
  • *STREPTOGRAMIN B**
  • *(B) Quinupristin**

BINDING SITE & MoA

A

QuinuPristin binds in the:
EXIT TUNNEL
&
PREVENTS the EGRESS of newly made protein

26
Q
  • *STREPTOGRAMIN A**
  • *(A) DalfoPristin**

BINDING SITE & MoA

A

Dalfopristin binds in the:
Peptidyl Transferase Center
&
Inhibits AA polymerization

27
Q

STREPTOGRAMINS
(A) DalfoPristin + (B) QuinuPristin

MoA

A

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
Q

STREPTOGRAMINS
(A) DalfoPristin + (B) QuinuPristin

Mechanisms of Resistance

A
  • *Drug Modification**
  • VAT AcetylTransferase** –> *inactivates Dalfopristin
  • *Vgb Lyase** –> opens the central circle of quinupristin
  • *Ribosome Modification**
  • *ERM methyltransferase** –> dimethylation of A2058
  • *Drug Efflux**
  • *VGA & LSA** = streptogrammin A
  • *MSR** = macrolides & streptogramin B
29
Q

What is:
VAT AcetylTransferase

what does it do and to what?

A

Mechanism of Resistance = Drug Modification

INACTIVATES** & **MODIFIES

DALFOPRISTIN
Streptogramin A

30
Q

What is:
VGB LYASE

and what does it do to what?

A

Mechanism of Resistance = Drug Modification

Opens the CENTRAL CIRCLE component of:
QUINUPRISTIN
Streptogrammin B

31
Q

What drug classes act on the
LARGE RIBOSOMAL SUBUNIT?

A

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
Q

What Antibiotic?

A

PLEUROMUTILINS
PleuroMutilin + RetapaMulin + LefaMulin
Complex DITERPENE Structure

TOPICAL
for
Skin infections = Impetigo / Wounds / Lacerations

Gram-Positive Pathogens

33
Q

PLEUROMUTILINS
PleuroMutilin + RetapaMulin + LefaMulin

Binding Site & MoA

A

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
Q

Mechanisms of Resistance

PLEUROMUTILINS
PleuroMutilin + RetapaMulin + LefaMulin

A
  • *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
Q

What do
VgaC & VgaE
do? and to what AB’s?

A

EFFLUX PUMPS
mechanisms of resistance for:

Streptogramins** + **Lincosamides** + **Pleuromutilins

36
Q

What Antibiotic?

A

4,6 - Substituted AMINOGLYCOSIDE
Kanamycin / Gentamicin / Tobramycin / Plazomicin

TB / Plague / Endocarditis

Aerobic GRAM-NEG
MycoBacteria

Usually in combo with Beta-Lactams

37
Q

What Antibiotic?

A
  • *4,5 - Substituted AMINOGLYCOSIDE**
  • *Neomycin** / Paromycin

TB / Plague / Endocarditis

Aerobic GRAM-NEG
MycoBacteria

Usually in combo with Beta-Lactams

38
Q

AMINOGLYCOSIDES
Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin

Site of Action

A

Act on:

  • *Small Ribosomal Subunit**
  • flexibility of AG’s allow their* adaptation to shape of binding pocket

Binding –> induces conformation of DECODING CENTER

39
Q

AMINOGLYCOSIDES
Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin

MoA

A

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
Q

AMINOGLYCOSIDES
Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin

Mechanism for SELECTIVITY

A
  • *Nucleotide 1408** of the Small Subunit is:
  • *A in BACTERIA**
  • but B in Eukaryotes*

Adenine @ this position is REQUIRED for TIGHT binding of AG’s

41
Q

AMINOGLYCOSIDES
Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin

Side Effects & WHY?

A

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
Q

AMINOGLYCOSIDES
Neomycin + Paromomycin // Kanamycin / Gentamicin / Tobramycin

Mechanisms of Resistance

A

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
Q

What AB?

A

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
Q

What AntiBiotic?

A

TETRACYCLINES
2nd Gen = Doxycycline + Minocycline

BOTH
Gram-Pos & Gram-Neg

lyme disease + CAP
Syphilis

45
Q

What Antibiotic?

A
  • *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
Q

How do Tetracyclines have GRAM-NEG activity?

A
  • *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
Q

What is CRITICAL for Tetracycline Activity?

A

STEREO-ORIENTATION
of the DimethylAmino-Moitety

Epimerization –> reduces activity of TetraCyclines

Ring A can undergo enolization & re-protonization

4-epitetracycline = inactive

48
Q

TETRACYCLINE

MoA

A

Tetracycline acts on the:
Small Ribosome and Blocks binding of AminoAcyl-tRNA

  • *Tigecycline TAIL** –> forms additional interactions
  • *20x affinity** vs tetracycline
49
Q

TETRACYCLINE

Mechanisms of Resistance

A

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
Q

What Antibiotic?

A

RIFAMPICIN

Potent + Broad-Spectrum AB
used in:
Anti-TB combination therapy
RED COLOR

BacteriCIDAL

51
Q

RIFAMPICIN

Target?

A

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
Q

Mechanisms of Resistance

RIFAMPICIN

A

Mutations in GENE ENCODING
on the
beta-subunit of RNA polymerase

53
Q

What Antibiotic?

A

SULFONAMIDE

Synthetic BacterioSTATIC AB’s
that mimic / structural analogs of
PABA
an intermediate of the FOLATE biosynthesis Pathway

54
Q

Sulfonamide
Sulfamethazole

Target / MoA

A

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
Q

Improvements in SULFONAMIDES

A

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
Q

What Drug?

A

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
Q

Trimethoprim

Target / MoA

A

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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