12 Antimicrobial drugs Flashcards
The lectures on antimicrobials will cover
Lecture 1: Antibiotics
Lecture 2: Antifungals
Both 1 & 2 will also discuss mechanisms of resistance against commonly used antimicrobials
Learning Outcomes
Know the main classes of antimicrobials with examples of commonly used representatives
Know and understand the mechanisms of action of commonly used antimicrobials
Know the mechanisms leading to resistance to commonly used antimicrobials
A bit of history – the discovery of penicillin
Alexander Fleming (1881 - 1955) Colony of Penicillium notatum S. aureus cells dying Colonies of Staphylococcus aureus
The medical application of penicillin required
a lot of additional efforts
Alexander Fleming (1881 - 1955)
Howard Walter Florey (1898–1968)
Ernst Boris Chain (1906–1979)
Collectively were awarded the Nobel prize in 1945
Antibiotics’ characteristics
Effect on bacteria:
killing bacteria – bactericidal
inhibiting/arresting growth of bacteria – bacteriostatic
Range of bacterial species affected:
a large number of bacterial species - broad spectrum
a limited number of bacterial species - narrow spectrum
a single species – limited spectrum
Characteristics based on target/mode of action
Antibiotics interfere with/inhibit essential cellular structures/processes
Antibiotics target bacteria-specific structures/processes
Such modes of action make them
Toxic to bacteria only
Innocuous to humans (little or no-side effects)
The cell wall is a target for many antibiotics
The CW is responsible for cell integrity
The CW protects bacteria from toxic substances
Absence of functional CW = death (by autolysis)
Human cells do not have cell walls
The cell wall is an essential bacteria-specific organelle
Bacterial species differ in CW structure
and composition
A simple test (Gram staining test) reveals CW differences
+ve (stained purple)
Staphylococci
Streptococci
Enterococci
ve (coloured pink)
Escherichia coli
Pseudomonas
Salmonella
The CWs of Gram +ve bacteria have thick layers of peptidoglycan chains
~40 Peptidoglycan (PG) chains linked together
Each peptidoglycan chain is build up of covalently linked sugars
NAM = N-acetylmuramic acid NAG – N-acetylglucosamine
Sugars linked in a chain
In addition short peptide chains are attached to NAM Peptide chains (3-5 aa)
Peptidoglycan chains cross-link via peptidyl bridges
Cross linking involves a large number of individual chains
It is an essential step in CW biosynthesis (especially in Gram+ve)
It is catalysed by specific enzymes
These enzymes, and the reactions they catalyse, are targets of antibiotics
In contrast, the CW of Gram ve bacteria have a thin PG layer
This helps explain why antibiotics targeting PG biosynthesis are not as effective against Gram ve bacteria
Antibiotics that act on PG biosynthesis
Beta ()-lactams -
Penicillins
Cephalosporins
Carbapenems
Vancomycin
-lactam antibiotics
are effective against growing and dividing cells
kill bacteria by autolysis (bactericidal)
resistant bacterial species produce -lactamase, a secreted enzyme which inactivates antibiotics by breaking down their -lactam ring
B-lactam antibiotics
Inhibit the enzymes involved in the transpeptidase cross-linking reaction
Interfere with linking the individual chains together
Disrupt PG synthesis leading to autolysis
B-lactam antibiotics
Penicillins
Natural (Penicillin G)
Aminopenicillin
(amoxicillin, ampicillin
Cephalosporins 1st (Cefalexin; cefazolin) 2nd (Cefaclor, cefuroxime) 3rd (Cefixime, cefpodoxime) 4th (Cefepime)
Carbapenems
Meropenem
Ertapenem
Imipenem
Key Characteristics
Penicillins
Very effective against Gram +ve
Some allergy reactions
Aminopenicilins better tolerated
Cephalosporins Different primary coverage: 1st – Gram +ve 2nd – Anaerobes 3rd – Gram –ve 4th - Pseudomonas
Carbapenems Broad spectrum Generally effective against all BUT: MRSA and VRE Only available IV
All are bactericidal
Vancomycin
An inhibitor of CW biosynthesis
different mode of action to beta-lactams
different chemical structure
Glycopeptide antibiotic
(more allergic reactions)
Effective against MRSA
Administered intravenously
However emerging cases of resistance
(VRSA; VRE)
Protein synthesis requires rRNA-Protein
complexes known as ribosomes
The ribosome has 2 subunits
There is no synthesis of proteins in the absence of
functional ribosomes
Bacterial ribosomes differ from those in humans
In bacteria = 30S + 50S
In humans = 40S + 60S
Examples of antibiotics which inhibit protein synthesis
Some bind to, and inhibit protein components of the 30S subunit
Tetracycline
Aminoglycosides (Gentamycin, Streptomycin)
Others bind to, and inhibit protein components of the 50S subunit
Macrolides (Erythromycin)
Chloramphenicol
Antibiotics inhibiting PS
Broad spectrum (effective against both Gram +ve and Gram –ve species) Most are bacteriostatic Associated with greater toxicity (human mitochondrial ribosomes are inhibited too)
Antibiotics inhibiting DNA biosynthesis
Fluoroquinolones
Common representatives
Fluoroquinolones ciprofloxacin norfloxacin levofloxacin moxifloxacin
Fluoroquinolones
Broad-spectrum, synthetic
Inhibit bacterial enzymes (DNA gyrase) with essential roles in DNA replication
Effective against Gram –ve bacteria and intracellular pathogens (Legionella, Mycoplasma)
Higher levels of toxicity associated with them
Antibiotics inhibiting RNA biosynthesis
RNA biosynthesis requires specialised enzymes known as DNA-dependent RNA polymerases
Rifampicin
Inhibits bacterial but not human RNA polymerases
Used predominantly for treating tuberculosis
Biosynthesis of nucleotides requires folic acid
DHPdiP (dihydropteroate diphosphate + PABA (para-aminobenzoic acid) Dihydropteroic acid - Bacteria but NOT humans can make folic acid Folic acid (Vit B9) dihydrofolic acid Tetrahydrofolic acid Synthesis of nucleotides DNA and RNA
Folic acid synthesis as a target of man-made antibiotics (antimetabolites)
Sulfonamides –
analogues of PABA, act
by substrate competition
Trimethoprim inhibits
dihydrofolate reductase
Co-trimoxazole – a mixture
of both (5:1), inhibits both
enzymes
Sources of commonly used antibiotics
Natural – produced by:
fungi: penicillin, cephalosporin
bacteria: erythromycin, rifampicin, streptomycin, tetracycline
Semi-synthetic – ampicillin
Synthetic – sulfonamides, trimethoprim
Choice of antibiotic treatment depends on:
bacterial species susceptibility to drug site of infection safety of drug cost of therapy patient factors
Resistance to antibiotics arises by
Mutations in bacterial chromosomal genes encoding targets of common antibiotics (VGT)
Transfer between organisms of resistance genes carried by plasmids (HGT)
Biofilm formation
Biochemically resistance is manifested by:
(i) decreased accumulation of the drug – increased efflux
or reduced permeability of the drug
(ii) enzymatic inactivation of the drug - secretion of - lactamase
(destroys beta-lactam) or chloramphenicol acetyl
transferase (inactivates chloramphenicol)
