Competitively inhibit folic acid synthesis - Humans unaffected as folic acid is a dietary supplement = Vit B9

Inhibitors of bacterial DNA gyrase/topoisomerase - responsible for supercoiling DNA - required for packaging DNA in bacterial cells + during DNA replication + transcription

Antibiotics Flashcards by Rosie Liddell

Antimicrobial drugs

Compounds that kill or control the growth of microorganisms IN the host

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Antibiotics

define
2 types

Compounds produced by 1 microorganism to kill or inhibit the growth of another microbe

Synthetic
Natural

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Bacteriostatic drugs
Bactericidal
Bacteriolytic

Prevent the growth of a microorganism
Compounds that kill the microorganism
Compounds that lyse the microorganism

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Major classes of antibiotics

Fungal:
Beta-lactams 
Penicillins
Bacterial:
Glycopeptides
Aminoglycosides
Tetracylines

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A good anti-microbial

= selectivity

Should kill or inhibit pathogen but not harm host

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Ideal drug target

A structure bacteria possess but humans don’t
e.g. peptidoglycan cell wall

Good not to affect normal host microflora

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Spectrum of drug activity

2 types
examples

Broad spectrum
= active against Gram- positive and Gram-negatives
e.g. tetracycline

Narrow spectrum
= only kills certain group of bacteria
e.g. vancomycin used to treat penicillin-resistant Gram-positives

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Antibiotic targets

RNA elongation 
DNA-directed RNA polymerase
Protein synthesis (50S + 30S inhibitors, tRNA)
Lipid biosynthesis 
Cytoplasmic membrane structure 
Folic acid metabolism 
Cell wall synthesis 
DNA gyrase

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Sulfanilamide

- strutcure

Structural analogue to para-aminobenzoic acid (PABA)

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PABA

Precursor for folic acid biosynthesis

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Folic acid biosynthesis

Needed for nucleotide biosynthesis

Bacteria have to synthesise own folic acid

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Sulfanilamide

- role

Competitively inhibit folic acid synthesis

Humans unaffected as folic acid is a dietary supplement = Vit B9

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Clinical resistance to sulpha drugs occurs

- then what happens?

2 drug combination:
Trimethoprim + sulfamethoxazole

Inhibits 2 sequential steps in folic acid biosynthesis
-> resistance less likely to arise

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Quinolones

- role

Inhibitors of bacterial DNA gyrase/topoisomerase

responsible for supercoiling DNA
required for packaging DNA in bacterial cells + during DNA replication + transcription

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Quinolones

- spectrum

Broad-spectrum

- all bacteria require DNA gyrase

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Quinolones

e.g. Ciprofloxacin

> Used to treat UTIs
Treatment of respiratory disease in farm animals
Drug of choice against Anthrax

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Beta-lactams

- role

Inhibitors of cell wall biosynthesis

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Beta-lactam antibiotics contain…

Produced by…

> Penicillins
Cephalosporins
Carbapenems

All contain beta-lactam ring
- but differ in chemical nature of 2nd ring + side chains

Fungi

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Penicillin

discovery
production

in 1928 by Fleming

Florey + Chain purified + conducted animal experiments
Pfizer developed use of large fermentation vats for commercial production

Beta-lactams

- mode of action

Irreversible inactivation of transpeptidases

- PBPs = penicillin binding proteins

PBPs

Catalyse transpeptidation + transglycosylation
= link between peptide side chains of peptidoglycan

Involves cleaving off the terminal D-Ala of the D-Ala-D-Ala end

Beta-lactams

- inactivating PBPs

Beta-lactam mimics D-Ala-D-Ala peptide bond

AB binds + irreversibly blocks active site of PBP

No cleavage of cell wall can occur

> no growth
> cells lyse

Beta-lactams

- only affect what cells?

Actively growing cells

Cell walls

Nearly all bacteria possess a PG cell wall
- In Gram-negatives it’s surrounded by outer membrane
= intrinsically resistant

Penicillins | - activity spectrum

Penicillin G can't penetrate outer membrane of Gram-negative Modification of N-acyl side group can change drug's properties - semi-synthetic drug

Penicillins | - Modifications of N-acyl side group can cause...

Broaden spectrum to include Gram-negatives Increase acid stability Impart beta-lactamase resistance

Antibiotic producers

Streptomyces - filamentous soil bacteria - produce 'geosmin' = damp forest smell Produce 90% of the 3000 ABs produced by Actinobacteria

Glycopeptides | - role

Inhibitors of cell wall biosynthesis - > bind to D-Ala-D-Ala - > blocks transpeptidation + transglycosylation

Glycopeptides | - structure

Large, complex moleucles Glycosylated, cyclic peptides synthesised by large multi-protein complexes Non-ribosomally synthesised peptides

Glycopeptide | - most important member

Vancomycin

Glycopeptides - target - when is this useful?

Same as beta-lactams but different mechanism = cell wall Treatment of beta-lactam resistant infections

Glycopeptides | - spectrum

Narrow spectrum | - only active against some Gram-positive bacteria

Glycopeptides | - issues

Toxic to humans | + strong side-effects

Aminoglycosides | - role

Inhibitors of protein synthesis | -> targets 30S subunit of bacterial ribosomes by binding to 16s rRNA

Aminoglycosides | - mechanism of action

Interferes with peptide elongation + translational proof-reading -> truncated + aberrant proteins in cell = non-functional

Aminoglycosides | - type of AB

Bactericidal

Aminoglycosides | - e.g.

Kanamycin

Aminoglycosides | - spectrum

Broad spectrum | - mostly used if other drugs fail

Tetracyclines | - role

Inhibit protein synthesis

Tetracyclines | - mode of action

Interferes with 30S subunit and binds to 16S rRNA | -> inhibits binding of aminoacyl-tRNAs to A-site

Tetracylines - type of AB - characterised by

Bacteriostatic | Naphthacene ring system tetra + cyclins = 4 rings

Tetracyclines | - natural + semi-synthetic analogues made

By modifying side groups of naphthacene ring

Tetracyclines | - spectrum

V broad | - inhibits almost all Gram-Positive and negative bacteria

New ABs in the media | - New AB discovered

New method for culturing bacteria from soil (new approach) - > discovered Teixobactin (new drug) - > targets Lipid II (old target)

``` New ABs in the media - New class of AB ```

Culture-independent method using DNA extracted from soil (new approach) - > Malacidins (new drugs) - > Targets Lipid II (old target)