Antimicrobials Flashcards
Penicillin discovery
It was discovered in 1928 by Alexander Flemming. Bacteria was streaked onto a plate, a fungi was also found growing on the plate. It formed a protective zone around it preventing bacteria from getting near it. This was found to be due to penicillin.
Florey and Chain were able to isolate it and improve activity.
Dorothy Hodgkin found penicillins atomic structure, helping us design derivatives.
General Cell wall targeting antibiotics
Penicillin, Cephalosporins, Carbapenems. These are broad spectrum antibiotics. They do not need to enter cells. Considered bacteriolytic, causing cells to lyse.
Gram (-) cell wall targeting antiobiotics
Monobactams. Do not need to enter cells. Bacteriolytic, lysing cells.
Gram (-) Protein synthesis targeting antibiotics
Aminoglycosides. Enter cells. Target the 30S ribosome subunit. Bacteriolytic, causing cell lysis.
Gram (+) Protein synthesis targeting antibiotics
Macrolides. Enter cells. Target 50S ribosome subunit. Bacteriostatic, arresting bacteria in a certain stage.
Target DNA replication in any bacteria.
Fluoroquinolones. Enter cells. Broad spectrum antibiotics. Bacteriolytic, causing lysis.
Gram (-) cell wall
Inner membrane, thin peptidoglycan layer, outer membrane. Outer membrane has carbohydrates. If the PG layer were thick, then proteins could not connect the inner and outer membranes.
Gram (+) cell wall
Inner membrane, thick peptidoglycan layer.
Peptidoglycan
Peptidoglycan is a mesh of carbohydrates that form the cell wall of bacteria. These carbohydrates are cross-linked by peptides. The cross link is formed by PBP via transpeptidation. LT, NagZ, and AmpD cleave and remodel PG during cell division.
PBP cross-linking
The peptide enters the Active site, where a D-Alanine-D-alanine residue attacks the serine residue, forming a covalent bond. The Peptide chain of another carbon chain enters and attacks this covalent bond, forming a dimer with the peptide and freeing the active site.
PBP2 penicillin binding
Penicillin contains a Beta-lactam ring that is similar to the D-alanine-D-alanine residue. The Beta-lactam ring is able to attack the serine residue, forming a covalent bond. Since the next peptide chain can not attack this bond, the penicilin stays bound, preventing cross-linking. The bacteria can no longer form a peptidoglycan layer, meaning the bacteria can no longer resistant external pressure and pops.
All PBPs are targeted by PBPs.
Beta-lactam ring
Present in many cell wall targeting drugs, preventing the formation of serine covalent bonds in the active site, preventing cross-linking.
Ribosomes
In prokaryotes, ribosomes has 30S and 50S subunits. First, tRNA enters the P site, binding the start codon, and another enters the A site. The Amino Acid from the first tRNA has a peptide bond formed with the A site amino acid. The first tRNA leaves and then second one moves to the P site allowing for a new tRNA to enter and bind its Amino acid. This continues until the exit codon is reached where a tRNA without an AA enters.
Aminoglycosides
They were isolated from the bacterium, streptomyces (Streptomycin). It is a very effective drug against gram negative bacteria, targeting the 30S subunit.
It works against some mycobacterium and gram positives.
It enters via polar interactions with the outermembrane. It goes through the cell wall via membrane transporters. It passes the inner membrane by oxygen dependent active transport.
It binds to 30S at the A site, preventing tRNA binding. Stopping protein synthesis, forming truncated peptides.
It is Bacteriocydal as it stays bound for a long time, causing cell death.
Macrolides
These target Gram positive bacteria 50S ribosomes. It is impermeable to the outer membrane. But it can freely diffuse through gram positives PG layer and membrane.
It binds between the A site and P site of the 50 ribosome, preventing peptide bonding for AAs, stopping synthesis.
It is bacteriostatic as it only stays bound for a short amount of time, freezing growth and weakening the bacteria.
Tetracyclines
These attack both gram positive and gram negative bacteria. It was isolated from streptomyces. It contains a 4 ring structure. It binds to the A site of the 30S ribosome, preventing protein synthesis.
Fluoroquinolones
These are entirely synthetic drugs. They can freely diffuse into bacteria, being able to target both types. It was originally made as a biproduct of an antimalarial drug.
It targets DNA. it has 2 rings surrounded by different variable sites that can be changed for specificity. It has two sites (F and Carboxyl group) that can not be changed. It targets DNA gyrase and topoisomerase, causing DNA fragmentation and replication inhibition.
Teixobactin
This drug was recently produced by looking at soil bacteria. It is currently going through clinical trials.
They found it by isolating bacteria and putting individual bacteria in wells. Bellow each well is a gram positive bacteria. This would allow any product from the bacteria to land on the strain below. They found Teixobactin which worked as an antibiotic.
It can freely diffuse into any bacteria. It can kill S. aureus without any development of resistance.
Teixobactin takes lipids from the membrane to form its own filaments, a chain of lipids. This forms around the bacteria, forming a protective sheet, preventing movement and survival. This also prevents cell division by acting as a glue
Antimicrobial resistance
The 1950s were the golden age for Antibiotics, in terms of efficiency and profits. By the 1970s the market was saturated and GPs reported resistance. After the discovery of Penicillin in 1928, by the 1940s there was resistant Staphylococcus aureus
Animal contribution to AMR
When animals are given antibiotics, their bacteria can develop resistance. Then the food produced can carry resistant bacteria.
Key resistant bacteria in hospital deaths
E. coli, Klebsiell pneumoniae, enterobacter faecium, psuedomonas aeruginosa, Methicillin resistant staphylococcus aureus (MRSA).
Becoming resistant
First there is a lot of bacteria with a few resistant bacteria. Then Antibiotic is applied and the non-resistant bacteria and good bacteria are killed. The surviving resistant bacteria can proliferate. They can then give their resistance to other bacteria.
Vertical evolution
A mutagen causes mutagenesis, generating antibiotic resistant bacteria by having modifications in the AB target. This can also be spontaneous.
Horizontal evolution.
Conjugation - A plasmid containing the resistant gene is carried by a bacteria and can be transferred to other bacteria.
Transformation - When the bacteria dies, the DNA is fragmented and the fragment carrying the resistance gene can be uptaken into a new cell.
Transduction - A phage can have the resistance gene in its DNA that it injects into the bacteria. This DNA can form a plasmid or be incorporated into the chromosome.
