Antibiotics Flashcards
What are some types of antimirobial agents?
They are defined as antibiotics (naturally occurring), chemotherapeutic agents (synthetic) or semi-synthetic (based on naturally occurring agents but with alterations).
Semi-synthetic drugs can alter pharmacological properties of naturally occurring antibiotics to:
- change the kinetics
- reduce toxicity
- modify antimicrobial spectrum
Furthermore, it can be used to extend a patent and make money for pharmaceutical companies.
How are some antibiotics classified?
Antimicrobials can be classified by source (natural/synthetic), by pharmacological class or by their broad mechanisms of action (how they affect bacterial growth - bacteriostatic or bactericidal).
What is the difference between bacteriocidal and bacteriostatic?
Bacteriostatic do not kill the bacteria, but instead arrest the reproduction of bacteria.
Bactericidal must cause a 3 log reduction (99.99% lethal).
If the bacteria stop growing in the host, then the host immune system is able to overcome the infection and kill the bacteria without the side effects of bactericidal antibiotics.
Bactericidal must be used in immunocompromised individuals as they have no immune response.
What are some general features of tetracyclines?
- Tetracyclines: Naturally they are eliminated quickly in the body, so by synthetically altering the kinetics of the drug so as to make it more convenient.
What are some general features of beta-lactams?
- Beta-Lactams: many different types of B-Ls. Includes the penicillin group and the cephalosporin group of antibiotics. [know the structure of Penam]
Give a history of the features of penicillins?
Many of the beta-lactams are derived from naturally occurring antibiotics but are in fact semi-synthetic.
The original Penicillin was Penicillin G. Has no toxicity unless an individual is allergic. (So okay for pregnancy, infants etc.) However it must be injected because it is acid labile and would be destroyed in the stomach. It is a painful injection (unpleasant for children). The addition of a small group onto the corner of the molecule allowed the penicillin to become acid stable and now it is able to be ingested orally. (Penicillin V)
Penicillin G and V work on Gram positive cocci and rods, however resistance trains of Staph. aureus and Strep. emerged in hospitals where many infections were treated ‘in bulk’. The process of treating with Penicillin was actually selecting for resistance. Methicillin was used for these resistance strains however it was more toxic (could cause renal toxicity) and so they attempted to synthesize a new form that was less toxic. Now, Staph. aureus can become resistant to this and are referred to as Methacillin resistant Staph. aureus (MRSA) - suggesting it is resistance to all beta-lactams.
Ampicillin has a broader spectrum and is active over Gram negative rods as well as that which Penicillin targeted. Amoxycillin is now used, which has a slightly different structure however it bears no clinically significant difference.
What is selective toxicity?
Drug that affects the microbe without affecting the host. Some antibiotics that affect the host can be used as anti-cancer drugs as they target the abnormal elements of cancer.
What are some targets of microbial agents?
Cell wall: beta lactams, glycopeptides (great target for antibiotics as it targets peptidoglycan synthesis)
Cytoplasmic membrane: polymyxins, polyenes- effective for fungi treatment (not a great target because of the similarity between the bacterial and host cell membrane)
Ribosomes: aminoglycosides, chloramphenicol, tetracyclines, macrolides
Nucleic Acid: rifamycins, quinolones (act on different stages/targets of Nucleic acids ie. transcription, folding etc.)
Folic Acid: suphonamides, trimethoprim (synthetic agents that interrupt with the synthesis of folic acid; we cannot make folic acid naturally but bacteria can so this is a selective targeting mechanism)
What is the general structure of peptidoglycan?
- Made up of two sugars (N-AG and M-AMA) to give layers of sugar that are cross linked by a peptide.
In Staph. Aureus, explain the structure of peptidoglycan?
- Because humans cannot make D amino acids, the alternating D and L in the peptidoglycan causes the rigidity of the cell wall.
- This molecule is on the outside of the bacteria. The blocks of the peptidoglycan are produced internally in the cell and then transported to the outside one block at a time.
Explain the biosynthesis of peptidoglycan.
- precursors synthesised from intermediated in cytoplasm
- Becomes immobilised on inner aspect of plasma membrane
- Synthesis of building block continues
- When complete, ‘building block’ transported to exterior aspect of membrane
- Linked to growing peptidoglycan chain
Peptidoglycan is capable of cross linking:
- Drugs can bind the enzymes that catalyse the cross-linking of peptidoglycan.
- Enzymes include transpeptidases or penicillin binding proteins and many others. This is because of the many varieties of cell walls.
What is the action of vancomycin?
Action:
Discovered long ago, not really useful until MRSA came along and now it is used to treat it.
It binds to D-ala, D-ala which is found on Staph. aureus peptidoglycan.
It doesn’t act on gram negative bacteria at all because it is so big and so charged.
What are some resistance mechanisms of vancomycin?
Resistance mechanisms:
The baceria can change the attachment site from D-ala-D-ala to have a sugar component. This is often found in enterococci.
If Staph. aureus develops resistance in this fashion to vancomycin, then there would be very limited treatments. It did occur- VRSA. They are very rare and appear to have died out on their own due to the energy strain of adding a sugar component.
It can produce another type of resistance. VISA (Vancomycin Intermediate-resistance Staph. aureus) has far more cell wall which affects the binding capacity of the Vancomycin by acting like a sponge to absorb the Vancomycin.
What are the actions of beta-lactams?
Action:
Penicillin mimics the D-ala-D-ala bond that causes the transpeptidase enzymes to bind penicillin instead of causing cross-linking. This inactivates the enzyme. Thus penicillin is a suicide inhibitor.
Penicillin is a bactericidal drug because of the mechanisms of the bacteria to constantly monitor cell wall production. Without the cell wall, the hypertonic nature of bacteria causes the influx of water into the cell which swells up and are then killed by osmotic lysis.
What is a resistance mechanism for beta-lactams?
- Beta-lactamase - produced by bacteria to overcome the effects of beta-lactams; can be overcome by types of beta-lactam that inhibits the action of only plasmid inherited beta-lactamase; clavulanic acid. (P. Auruginosa has chromosomal lactamases and cannot be overcome)
- altered penicillin-binding proteins
What is the action of beta lactamase?
The antibacterial spectrum of beta-lactam antibiotics varies greatly because bacteria have different PBPs. The accessibility of the antibiotic to PBPs varies and the susceptibility of antibiotic to beta-lactamase varies.
Name some antibiotics that act on protein synthesis.
Recognition: aminoglycosides, tetracyclines
Peptidyl transfer: chloramphenicol
Translocation: macrolides
Isoleucyl-tRNA synthesis: mupirocin
Formation of initiation complex: oxazolidones
What are some features of aminoglycosides?
Aminoglycosides are typically used topically or orally by GPs, but they are important in hospitals for serious infections.
Streptomycin was the first drug used for TB, but now we have gentamycin and tobramycin (naturally occurring) as well as amikacin (synthetic).
The drugs interfere with recognition by binding where the amino-acyl transfer RNA would bind and destroying the site.
What are some mechanisms for modification of aminoglycosides?
Modification of Aminoglycosides:
Any one of these will inactivate the aminoglycoside. They are highly charged and are not very soluble in bacterial cell wall. They initially cross in small []s and then when the structure is damaged, it can cross in larger []s.
Adenylation:
Phosphorylation: { all of these lead to a lack of ability to enter the cell}
Acetylation:
What is a resistance mechanism against aminoglycosides?
- Enzymes in the bacteria cause modifications to the drug
- Efflux is another mechanism where the drug is flushed from the bacteria
- Ribosomal mutations stop it binding ribosomes
What are some general resistance mechanisms to antimicrobial agents?
Drug inactivation
- By hydrolysis, e.g. β-lactams
- By covalent modification, e.g. aminoglycoside, chloramphenicol
Altering the target of drug action
- Modify target to a less sensitive form, e.g. β-lactam, vancomycin
- Overproduce target, e.g. vancomycin
Reduce access of drug to target
- Reduced entry into cell, e.g. aminoglycosides
- Increase efflux from cell, e.g. aminoglycosides, tetracycline
Failure to activate inactive precursor of drug
- e.g. metronidazole (synthetic pro-drug that is activate by nitro-reductase which is found in anaerobic microbes - easily overcome with microbial resistance), isoniazid (frontline treatment for TB)
What are some examples of antibiotic resistance bacteria?
- Methicillin-resistant Staph. aureus (MRSA)
- Penicillin-resistant pneumococci (PRP)
- Vancomycin-resistant enterococci (VRE)
- Vancomycin-intermediate-resistant Staph. aureus (VISA)
- Carbapenem-resistant Enterobacteriaceae (CRE)
- Multidrug-resistant Gram-negative rods
- Hypervirulent Clostridium difficile
- Multidrug-resistant Mycobacterium tuberculosis (MDR-TB)
- Extensively drug-resistant M. tuberculosis (XDR-TB)
What is the genetic basis for resistance?
The genetic basis of resistance can be intrinsic or extrinsic (via mutation or horizontal gene transfer) (Intrinsic: Pseudomonas A. has intrinsic resistance towards most early class beta lactams; Enterococci are intrinsically resistant to sulphanomides because they do not synthesize folic acid in a similar way that those drugs don't affect humans because we do not synthesize folic acid.)
Explain transformation.
- In transformation, the cell is lysed and the fragments of DNA are taken up by competent bacterium which incorporate that DNA into their genome. Many bacteria aren’t naturally competent and must be activated in a lab setting if they are to take up the DNA.
- Bacteria are also anxious about taking up DNA; have an ‘immune system’ that is made up of DNA methylation and restriction enzymes(ECHO R1; SOW 3A) - this allows the bacteria to only take in DNA which is related in some way to the innate genetic material of that bacteria.
- higher numbers tend to be less virulent because the more virulent forms are found/discovered earlier and thus given the early letter/number categorization.
- The most resistant of bacteria are within our body because they are often exposed to antibiotics. These bacteria can transfer resistance to other more dangerous types of bacteria. For example Staph. Epidermidis is highly resistant and it can transfer resistance to pathogenic bacterial infecting agents (ie. pneumococci)
