Session 11 - Lecture 1 - Antibacterials Flashcards
1 - Title
Antibiotics
Dr David Jenkins
Prescribing principles
2 - LO
Overview • Why antimicrobials are unique • Antibacterials: when and how to use them • Problems with antibacterials • Conclusion
“Terminology: Antibacterials are a type of antimicrobials (antimicrobials include antivirals, antifungals etc) Antibiotics pretty much synonymous with antibacterials for purposes of this lecture (tiny pedantic differences you don’t need to know).”
3 - The unique property of antimicrobials
The unique property of antimicrobials
Antimicrobials target microbial biochemistry
The ideal antimicrobial would have no direct impact on patient biochemistry or physiology
“targets microbial biochem - might sound fairly obvious but point is that this has no impact on the host pt biochem or phys. Also, as microbes are transferable from person to person means resistance is also transferable. So clinically, important thing to recognise in terms of antimicrobials is how you treat one pt can affect the success of how you treat other pts, unlike other drugs such as beta blockers for heart disease – if treating a pt badly with anything other than microbial then won’t affect the outcome of other pts – but bc of the issue of resistance means it can adversely affect their pts bc of transferrable resistance.”
4 - How do antibiotics work?
How do antibiotics work?
• Antibiotics work by sticking to specific bacterial molecules, interfering with their shape and consequently their function
- Cefipime, a cephalosporin antibiotic binding to DD-transpeptidase (large grey molecule)
Image from: Mahasenan KV et al. J Am Chem Soc 2017;139:2102-2110
“V much like other drugs, abs bind to specific sites – these aren’t just general poisons like disinfectants (type of non-selective antimicrobial, e.g. bleach)
[IMG] Can see a v small molecule (cephalosporin the antibiotic) big grey molecule is DD-transpeptidase aka penicillin-binding protein (named from observation from treating pts with penicillin, not what its original function was).”
5 - How does penicillin work?
How do antibiotics work?
• For example, penicillin binds to DD-transpeptidase, a bacterial protein that is vital for making the outer cell wall of bacteria.
• As a result of penicillin’s action, the cell wall is weakened and the bacteria burst
- Polysaccharide chain
- Peptide
- Active DD-transpeptidase
- Polysaccharide chain
- Penicillin
- Inactivated DD-transpeptidase
Illustration from: Lobanovska M and Pilla G, Yale J Biology and Medicine. 2017;90:135-145
“You can see the penicillin fitting into DD-transpeptidase, once it fits into it, inactivating it. The cross-linking for the gram positive cell wall production, therefore confounds the function and it’s destroyed, it’s intervened, it’s prevented – the cell wall is weakened, bacterial contents burst out – and that’s how penicillins work – they’re cell wall inactivators.”
6 - Draw a typical bacterium
- Capsule
- Cell wall
- Plasma membrane
- Cytoplasm
- Ribosomes
- Plasmid
- Pili
- Bacterial Flagellum
- Nucleoid (circular DNA)
“So there’s a wide class of antimicrobials/antibacterials rather – going to illustrate the point of action in a number of them. THis first slide is an Ideal bacterium, lots of potential targets here”
7 - Antibiotic targets (1)
Antibiotic targets
- Capsule
- Cell wall
- Plasma mmebrane
- Cytoplasm
- Ribosomes
- Plasmid
- Pili
- Bacterial Flagellum
- Nucleoid (circular DNA)
- DNA synthesis
Quinolones
- ciprofloxacin
Folic acid antagonists
- trimethoprim
- sulphonamides
“DNA of bacteria is not enclosed within nuclear membrane – free within the cytoplasm as one big circle of DNA. But otherwise DNA synthesis needs NTs etc just as in eukaryotes.
1. Quinolones, ciprofloxacin interferes with DNA gyrase which controls the winding and unwinding of bacterial DNA.
2a.. Trimethoprim as a single agent used for UTIs (major use)
2b. sulphonamides as an antibacterial agent is combined with trimethoprim – it is not normally given alone. “Co-“ means a combination drug (when Co followed by a hyphen). Co-trimoxazole which is trimethoprim and sulphonamide,
Trimethoprim work by inhibiting of folic acid and NT synthesis, therefore interfere with the production of bacterial DNA.”
8 - Antibiotic targets (2)
Antibiotic targets
- Capsule
- Cell wall
- Plasma membrane
- Cytoplasm
- Ribosomes
- Plasmid
- Pili
- Bacterial Flagellum
- Nucleoid (circular DNA)
- Protein synthesis
Aminoglycosides
- gentamicin
Macrolides
- erythromicin
Tetracyclines
“Moving out into the cytoplasm a bit more, we’re looking at attacking the ribosomes. Now Bacterial ribosomes overall in general principle they’re the same as eukaryotic ribosomes, just a different size - 16S vs 18S size in eukaryotes – therefore structure slightly different which is enough to make selectively poison antibiotics. Tetracyclines e.g. doxycyclin. All classes listed inhibit protein synthesis and therefore inhibit other vital metabolic pathways downstream.”
9 - Antibiotic targets (3)
Antibiotic targets
- Capsule
- Cell wall
- Plasma membrane
- Cytoplasm
- Ribosomes
- Plasmid
- Pili
- Bacterial Flagellum
- Nucleoid (circular DNA)
- Cell wall synthesis
Beta-lactams
- penicillins
- cephalosporins
- carbopenams
Glycopeptides
- vancomycin
“Moving out into the cell wall, already mentioned Penicillin which isa beta-lactam group of antibiotic, and they all work by inhibiting or interfering with cell wall synthesis. Similarly, another important group of antibiotics specifically targeting gram +ve organisms are the glycopeptides – vancomycin is one. Typoplaynin(?) is another glycopeptide – these all act at the cell wall level. So actually when you think about it, I said at the beginning there’s a wide range of antibiotics, actually there isn’t such a wide range – their targets are fairly limited. Actually we’ve run out of antibiotics, haven’t found any new classes since 1987, actually lots of new policies pin their hope on new antibiotics, but there’s no new logical reason why these classes shouldn’t exist – doesn’t necessarily mean they will end up with success, who knows whether we will have any new classes.”
10 - Types of antibiotics
How do antibiotics work?
• There are many different types of antibiotics.
• They vary in structure, in their mechanism of action and in their activity against different bacteria
Site of action / Examples of antibiotics
Cell wall synthesis:
- Beta-lactams (penicillins, cephalosporins, carbapenems).
- Glycopeptides (vancomycin, teicoplanin)
Protein synthesis
- Aminoglycosides (gentamicin).
- Macrolides (erythromycin).
- Tetracyclines (doxycycline).
DNA synthesis
- Quinolones (ciprofloxacin).
- Folic acid antagonists (trimethoprim, co-trimoxazole)
“Just to sum up a bit here, so Abs work, diff types of varying molecular structures - Do not need to remember the structure of antibiotics for clinical medicine (definitely no!) - just need to know the different classes are bc of different structures. You modify side chains and that gives you as lightly different property, but basic structure of Ab determines its activity - Vary in methods of action bc of structural differences and consequenrly in their activity against diff bacteria. Some antibiotics tend to be more active against g -ve, some g+ve etc. Reason for that is v straightforward - Gram stain reflects differences in cell wall, and those diff in cell wall structure allow the mechanisms of Abs against cell wall or not. But the gram stain is a very useful test in the lab – one of the first things we’ll do in the lab is take a drop of blood from a positive bottle, put it into a glass slide, gram stain takes a couple of minutes to do, be able to see wether there is g-ve or+ve bacteria. Gram stain tells us how successful the antibiotic will be. So if we grow g -ve bacteria and vancomycin is used then we would know that this is ineffective as it acts on g +ve bacteria so all g -ve are resistant to vancomycin. Not that clear cut but generally general rule. “
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