PMC III

Antibiotics
Review
Structures
 General Structures of b-Lactams
All have a b-lactam. A square

Penicillin  Pentagon Carbon in the pentagon  Carbapenem

Cef sounds like six  six-member ring Mono = one  there is only one
Cephamycins
(2nd generation cephalosporins) 3rd Generation Cephalosporins
H3C

Cephamycin

5th Generation Cephalosporins

N
S
N
R
Vancomycin Daptomycin Polymixin
a lipopeptide
A glycopeptide
Bacitracin Rifamycins
Lincosamides Macrolides

Lincomycin

15 member
Oxazolidinones Tetracycline Structure
H3C CH3
HO CH3 N
H H
OH

NH2

OH
OH O OH O O

Tetracycline
Aminoglycosides Fluoroquinolones

4
3
1
 “Nitro” drugs Sulfa Drugs

O2N
 MOA
b-lactams
• b-lactams inhibit transpeptidase
• Resemble D-Ala-D-Ala
• Irreversible

b-lactamase
• Inactivates the β−lactam by splitting the cyclic amide
• Reversible
 MOA
-vancins Bacitracin
• Binds NAM & NAG building blocks at D-Ala-D-Ala • Inhibits bactoprenol, a membrane protein that carries
• Pevents cross linking of peptidoglycan layer the cell wall building blocks

Daptomycin Cycloserine
• Lipophilic tail inserts into membrane • Inhibits Ala racemase and D-Ala-D-Ala ligase. The first
• Binding Ca2+ causes it to complex with other steps in cell wall biosynthesis
daptomycin molecules
• Forms a pore

Polymixins
• Bind LPS
• Disrupts outer and inner membranes as surfactants
 MOA
Cycloserine Daptomycin

Isoniazid

Bacitracin

Polymixins
Vancomycin

b-lactams

Macrolides and lincosamides
Bind to ribosomal 50s subunit
•Inhibits polypeptide exit (tunnel)
•Binds to 23s rRNA
•Inhibits translocation
•Inhibits transpeptidase reaction
Fidaxomicin
• MOA: blocks RNA synthesis by inhibiting
RNA polymerase
MOA
Quinupristin and dalfopristin
Inhibit peptidyl transfer
•Dalfopristin binds the 23S rRNA in the 50S
ribosomal subunit
•Conformational change
•Creates a high affinity binding site for quinupristin
Oxazolidinones
• Binds to 23S rRNA in the 50S ribosomal subunit in the A
site blocking the binding to 30S ribosome
• Blocks the start of protein biosynthesis
Tetracyclines
MOA “Nitro” drugs
• Bind to 16s rRNA in the 30s subunit • Nitro group is reduced to a radical anion which reacts
• Conformational change in 30S covalently with bacterial DNA, causing a bactericidal effect
• Inhibit aa-tRNA binding

Aminoglycosides Sulfa drugs

Bind to the 30s ribosomal subunit, interfere w/ protein
biosynthesis in a dual manner:
• Cause specific mis-reading of the codons on m-RNA,
therefore cause faulty and nonsense protein/enzyme
biosynthesis
• Cause premature release of proteins/enzymes from the
ribosome
Fluoroquinolones
Inhibit DNA Gyrase (Gram (-)) and Topoisomerase IV
(Gram (+))
Sulfas are analogs of PABA
They block synthesis of folic acid
• Sulfas inhibit Dihydropteroate Synthase
• Trimethoprim inhibits Dihydrofolate Reductase
Rifamycins
• Rifamycins bind DNA-dependent RNA-polymerase after
replication has initiated
• Binding causes a conformational change and the
polymerase dissociates from the complex after a few
nucleotides have been added
 Isoniazid/Pyrazinamide/Ethionamide
MOA Bedaquiline
• Prodrug
• Activated by KatG. Active species forms an adduct w/ Inhibits ATP synthase through binding to the C subunit
NADH
• Isoniazide-NADH adduct binds InhA and inhibits mycolic
acid synthesis

Ethambutol
Inhibits incorporation of mycolic acid into cell wall by
disrupttion of arabinogalactan synthesis in cell wall by
inhibiting arabinosyl transferase

p-Aminosalicilic acid
1. Prodrug that inhibits folate synthesis by binding
Dihydropteroate synthase more tightly than PABA
2. An inhibitor of cell wall synthesis. Prodrug that forms an
adduct with NADH
 Resistance
b-lactams Oxazolidinones
• Production of b-lactamase by bacteria Gram-Positive Bacteria
• Alterations in the molecular structure for PBPs •Decreased binding to the ribosome due to
of the bacteria changes in molecular structure
• Decreased antibiotic uptake by microbe  •Occasionally seen in the clinical setting
Gram-Negative Bacteria
porin inactivation (Gram (-))
•Intrinsic resistance due to efflux mechanisms
• Efflux (Gram (-))
•(Linezolid is not used for G(-) infections)
Macrolides, lincosamides, streptogramins (MLS B) Tetracyclines
•erm gene encodes for a methylase enzyme (erm • Bacterial production of a ribosome protective
= erythromycin resistance methylase) protein
•Methylation of a purine base in 23S rRNA of the • Protein allows ribosome to transcribe the m-RNA ,
even with tetracycline attached to the 30S subunit
binding site
• Efflux of Antibiotic from Microbe
• Decreased porin transport
 Resistance
Aminoglycosides Rifamycins
• Point mutation at the ribosomal binding site Resistance develops from a mutation in RNA pol that
• Decreased uptake of antibiotic results in inability of rifamycin to bind
• Production of transferases that inactivate the drug
• Acetyltransferases acetylate amino groups
• Phosphotransferases: phosphorylate -OH groups
• Nucleotidyltransferases: adenylate –OH groups
• NOT Amikacin

Fluoroquinolones
• Mutations in two genes (gyrA and gyrB), which code for the
target DNA gyrase
• Mutations in two genes (parC and parG), which code for the
target topoisomerase IV
• Drug efflux by resistant bacteria
• Decreased uptake by resistant bacteria