Lecture 13- Inhibitors of protein synthesis, nucleic acid synthesis Miscellaneous groups Antimicrobial susceptibility testing Flashcards
Q1. On this diagram,
polymyxin and Betalactams are listed together,
but what is distinct about
them?
Beta lactams target the cell wall whilst polymyxins target the cell membrane
Inhibitors of protein synthesis
Q2. What else, other than the structure of the ribosomes, may allow
antibiotics in this group to be selectively toxic?
you have scope for selective toxicity here as there are a lot of differences between bacterial and eukaryotic protein synthesis such as the ribosome subunits in bacteria and eukaryotes
its important to recognise that bacteria do not just bind to an important physical structure.
the drugs interrupt the processes, the enzyme, they interrupt, not just the structures, but any of the mechanisms involved in protein synthesis that differ between bacteria and eukaryotes
Aminoglycosides:
Q3. Can you recall some of the organisms
that cause these conditions (try and do this
without reference to your notes)?
- in order to remember where these are important it is good to recognise that the amino in aminoglycosides refers to amino acids which are used to affect protein synthesis
-The aminoglycosides primarily act by binding to the aminoacyl site of 16S ribosomal RNA within the 30S ribosomal subunit, leading to misreading of the genetic code and inhibition of translocation
The binding of aminoglycosides distorts the shape of the ribosome’s decoding region, specifically in the area responsible for checking the accuracy of tRNA binding. This distortion leads to:
Misreading of mRNA codons: The ribosome is no longer able to accurately match tRNA molecules to the correct mRNA codons, resulting in the incorporation of the wrong amino acids into the growing protein chain.
Production of faulty proteins: The misreading leads to the synthesis of non-functional or toxic proteins that can disrupt the bacterial cell’s normal functions.
Interruption of protein synthesis: The distortion can also cause premature termination of protein synthesis, leading to incomplete proteins.
Mechanism of Action of Aminoglycosides
Binding to the 30S Ribosomal Subunit: Aminoglycosides bind irreversibly to the 30S subunit of the bacterial ribosome, a key part of the protein synthesis machinery in bacteria.
Interference with Protein Synthesis: Once bound, aminoglycosides cause two main disruptions in protein synthesis:
Misreading of mRNA: They cause the ribosome to misread the messenger RNA (mRNA) template, leading to the production of faulty or non-functional proteins.
Premature termination of protein synthesis: They can also lead to the premature ending of protein chains, resulting in incomplete proteins that cannot function properly.
Bactericidal Effect: The production of these defective proteins disrupts bacterial cell membrane integrity and other cellular functions, ultimately leading to bacterial cell death. This makes aminoglycosides bactericidal, meaning they kill bacteria rather than just inhibiting their growth.
- there is a huge group of drugs in this class and they bind to bacterial ribosomes which end up distorting the structures of the ribosome, they prevent translocation so can stop the early process of protein synthesis
But there’s a few examples here that are sort of keynotes, examples that you should note, particularly gentamicin, streptomycin and neomycin, these are the main few that represent the different uses of aminoglycosides
these drugs are usually given intravenously and you need to be admitted to hospital in order to receive these drugs and usually you need your serum antibiotic levels checked because you have nephrotoxicity and ototoxicity if you have too high a concentration of this drug (ototoxicity is a toxicity that affects your hearing and can damage your hearing)
- these are strong drugs usually only reserved for very severe infections
-Streptomycin recovered briefly in the last lecture because that was that one that had that had the systematic instead of serendipitous discovery
-topical means it is something that you can apply to your external surfaces, thus if you have a skin or outer ear infection the drugs come in the form of eye drops or cream that you can directly apply to the surface of the skin, rather than take it orally
however important to note these drugs are inactive against streptococci and anaerobes. it’s also not really recommended as a sole agent for treating Pseudomonas infections either.
Q3.
each condition is caused by different or similar bacteria i.e e. coli fits a few of the conditions or listeria affects a condition, think about which diseases can cause these different conditions- staphylococcus aureus is a pathogen that fits the severe skin;bone;tissue infection
the aminoglycosides can bind to ribosomes and prevent protein synthesis initiation and because that’s such a universal property they have very good activity against a range of microbes so they’re very, very broad spectrum.
Inhibitors of protein synthesis Macrolides
the aminoglycosides can bind to ribosomes and prevent protein synthesis initiation and because that’s such a universal property they have very good activity against a range of microbes so they’re very, very broad spectrum.
Macrolides is another major group of drugs- these drugs bind to the peptide molecule that is bound to the tRNA so they interrupt the step in which bacteria try to incorporate new peptides, this causes the polypeptide chain to become disassociated from the ribosome
Macrolides are a class of antibiotics that work by inhibiting bacterial protein synthesis. They specifically target the bacterial ribosome, which is the cellular machinery that produces proteins. Macrolides bind to the 50S subunit of the bacterial ribosome, blocking the translocation step of protein synthesis. This action prevents the ribosome from moving along the mRNA, effectively stopping the production of essential proteins needed for bacterial growth and survival.
Key Features of Macrolides:
Mechanism of action: By binding to the 50S ribosomal subunit, macrolides interfere with the elongation of the protein chain, leading to incomplete or non-functional proteins.
Bacteriostatic effect: Macrolides are usually bacteriostatic, meaning they inhibit the growth of bacteria rather than directly killing them. However, at higher concentrations, they can have a bactericidal effect against certain pathogens.
Broad spectrum: They are effective against a wide range of bacteria, particularly Gram-positive bacteria and some Gram-negative bacteria, as well as atypical pathogens like Mycoplasma pneumoniae, Chlamydia spp., and Legionella spp.
Aminoglycosides are bactericidal
Macrolides: Mainly effective against Gram-positive bacteria
Macrolides have a Bacteriostatic effect
Aminoglycosides: Primarily effective against Gram-negative bacteria but lack activity against anaerobes and most gram-positive bacteria
aminoglycosides prevent protein translation, macrolides inhibit protein synthesis
Macrolides have a more specific effect in binding to that growing protein train. whereas aminoglycosides distorted the ribosome
macrolides are not quite as broad spectrum as the aminoglycoside
when referring to a broad spectrum list of microbes a prominent characteristic is that the antibiotic referred to as broad spectrum is able to kill microbes that are intracellular such as chlamydia as it is difficult to find antibiotics that not only get into the bacteria cells but before that, also get into the host cell so broad spectrum would refer to you having a good range of activity against a range of organisms
regarding antibiotic resistance if you have better patient compliance with the drug regime, you’re less likely to get resistance. and if you have to take 4 doses a day you’re much more likely to miss a dose, than you are if you only have one dose to manage so improving antibiotics by creating more efficient derivates even if they have the same mode of action is important and can also help control side affects better
a lot of the bacteria mentions on the slide affect the lungs by causing respiratory infections and its important to know in cases of a typical case of pneumonia you would be treated with a macrolide drug
so of the protein synthesis inhibitors the ones to remember here are:
for the aminoglycoside group- Gentamicin, Streptomycin and Neomycin
and for the macrolides group:
Erythromycin, Azithromycin and Clarithromycin
Inhibition of nucleic acid synthesis
nucleic acid synthesis inhibitor
why are there so many antibiotics against cell wall inhibitors, but so few against those that inhibit nucleic acid synthesis?
And the issue here is that there’s too many similarities in DNA and nucleic acid synthesis replication sacross for living organisms. So there’s fewer selective targets in bacteria that wouldn’t also affect our own DNA replication. And as a result of that, some research into some antimicrobials, has developed drugs with very high toxicity levels when given to mammalian cells so they were never developed as antibiotics but were developed as anti-cancer drugs which have to be more toxic by their nature and are usually less specific because they tend to eliminate all cells in a vicinity to hopefully eradicate any potential cancer cells
however why here are so many antibiotics against cell wall inhibitors, but so few against those that inhibit nucleic acid synthesis is that
There’s too many similarities here to allow selective toxicity between mammalian cells and bacteria
however the last bullet point here in the blue box, the inhibition of enzymatic processes- This is where most of our antibiotics come from, where there’s any kind of DNA perturbation. It’s the enzymes that bacteria use in DNA replication are slightly different from our own. so you can actually therefore achieve a selective toxicity. So if you can design a drug that inhibits bacterial enzymes in DNA replication then it’s not going have very high affinity with our own DNA enzymes. so there are 18 gene products involved in bacterial chromosome replication that do not have direct equivalents in mammalian cells- the particular enzyme that is most widely exploited to produce a selective target in bacteria are the enzymes in the gyrase
these drugs again have a broad spectrum of activity because well all bacteria will synthesise DNA in this way And if the drug can penetrate and get to the active site in the bacterium, then it’s able to exert its effect there.
Inhibition of nucleic acid synthesis- Quinolones
Q4. What properties may each new generation of antibiotic introduce?
Quinikines are the drugs that affect nucleic acid synthesis and they affect the enzymes topoisomerase, also referred to as gyrases and these enzymes, during the process in which DNA is being replicated whilst there’s super coiling occurring in the chromosome and, and the helix itself is also coiled the gyrase/topoisomerase will untangle that so that the strand can be split to allow for new nucleotides to be added as new DNA strands are being synthesised and so that is the function And if you don’t have the enzyme to do that, then obviously DNA synthesis stops and the cell will therefore lose its ability to function.
regarding which antibiotics to take note of Nalidixic acid as it was the first discovered however it is not commonly used clinically but rhwthe second generation ciprofloxacin is the most commonly used
but with he newer 3rd and 4th generation of the antibiotics we aim to developed drugs that have a more wide spectrum of activity so drugs that can also affect gram negative and gram positives wherase the second generation drugs here only tend to affect gram negatives
newer generation can also have better dosing, new R-groups on the drugs mean they may interact less with other drugs or enzymes which may reduce side effects as a lot of these patients receiving these drugs will already be very ill and receiving other drugs its important that we developed ones that can work together
So again basic principles then it’s the quinones effect DNA replication.
there’s a range of different generations of drugs that are modified to get better coverage and better patient outcomes for reasons to do with side effects.
Metronidazole
this is also a drug that has an affect on DNA, Its main area of damage is that it damages bacterial DNA. And it’s metronidazole. I’ts a very commonly prescribed antibiotic worldwide. Globally, it accounts for the majority of any antibiotic class that’s consumed. And that’s because most people here would probably take metronidazole If you’ve ever had wisdom tooth surgery or something like that, or dent abscess or something like that, you’d normally be taking metronidazole. because, it’s able to affect anaerobic bacterial cells. Um, and it’s um, unique in terms of treating things like gingivitis caused by dental surgery, and dental infections.
Diversity of protozoa:
Example of diverse characteristics:
Mitochondria are the “batteries” of eukaryotic cells. How can eukaryotic
cells with no mitochondria generate energy?
how do these protozoa actually respire if they don’t have, mitochondria? And the answer to that is that because they’re so early diverged from prokaryotic cells, they’ve actually retained all of the energy synthesis, enzymes and metabolism that would be present in a bacterium. So uniquely for a eukaryote, they actually respire using bacterial processes. Hence they might metronidazole works against both these kind of parasites and anaerobic bacteria well its because metronidazole inhibit the same process pretty much in the bacteria and protozoa organisms
So again, um, the bacterial genes encode enzymes for a fermentative metabolism. That’s the key part of that slide there. That’s the part that metronidazole will affect.
Q5. Why does
metronidazole not
damage human DNA?
What is the mode of
selective toxicity?
when metronidazole is in an anaerobic environment such as bacteria that are causing a dental abscess or even gut problems- And when the metronidazole gets to that part of the site and it gets inside the anaerobic bacteria it undergoes a redox reaction in that environment inside the bacterium and metabolites from that process are toxic and pull DNA fragments
Q5-
it does not affect human cells because our DNA is not typically in cells that are anaerobically respiring
we do not Respire anaerobically. So we don’t metabolise the metronidazole to produce these toxic metabolites.
How Metronidazole Works
Activation in Anaerobic Conditions:
Metronidazole is a prodrug, meaning that it is initially inactive and requires chemical modification to become effective.
The drug is activated only under anaerobic (low-oxygen) conditions, which are common in anaerobic bacteria and certain protozoa.
In these conditions, microbial enzymes called nitroreductases convert metronidazole into its active form by reducing its nitro group.
comparing metronidazole to the quinones
- The quinones effect enzymatic processes in DNA replication.
-Metronidazole exploits anaerobic fermentation pathways in bacteria in a way that damages DNA so completely different mechanisms of action. But both groups affect bacterial DNA
Metronidazole summary of important points
Anti-metabolites
Q6. How may trimethoprim be selectively toxic, if
it inhibits mammalian tetrahydrofolic acid?
this is a small group- there’s not that many in this group of anti metabolite synthesis inhibitors.
there are important antibiotics used to treat certain conditions such as UTIs which are very common types of infections so although it does not have a particularly broad spectrum it is still very widely used because of the type of infections it treats
- trimethoprim is a very important antibiotic
-it relies on the fact that folic acid is used to synthesise tetrahydrofolic acid in both mammals and bacteria, an essential nutrient used by both
whilst the DHFR that converts dihydrofolic acid to tetrahydrofolic acid exists in both bacteria and mammal cells and can be inhibited by the antibiotic and it appears there is a form of selective toxicity as the trimethoprim binds with massively more affinity to the bacterial form of DHFR than to the mammalian form of DHFR
Anti-metabolites SUMMARY SLIDE
the drugs are sometimes used together in order to get a more broader affect
The most important antimetabolite antibiotics are those that interfere with bacterial folic acid synthesis. These antibiotics target the metabolic pathways that bacteria use to synthesize essential molecules, thereby inhibiting their growth and survival. The two most commonly used antimetabolite antibiotics are:
- Sulfonamides (Sulfa Drugs)
Mechanism of Action: Sulfonamides are structural analogs of para-aminobenzoic acid (PABA), a key precursor in the bacterial synthesis of folic acid. These antibiotics competitively inhibit the enzyme dihydropteroate synthase, preventing the conversion of PABA into dihydrofolic acid, an essential step in the folate pathway.
Effect: By blocking folic acid synthesis, sulfonamides prevent bacteria from producing DNA, RNA, and other essential molecules.
Spectrum of Activity: Effective against a wide range of Gram-positive and Gram-negative bacteria.
Clinical Uses: Commonly used to treat urinary tract infections (UTIs), respiratory infections, and certain types of pneumonia caused by susceptible organisms.
- Trimethoprim
Mechanism of Action: Trimethoprim inhibits the enzyme dihydrofolate reductase (DHFR), which is responsible for converting dihydrofolic acid to tetrahydrofolic acid. This step is crucial for synthesizing nucleic acids and proteins.
Effect: By targeting a later step in the folic acid pathway, trimethoprim works synergistically with sulfonamides to block bacterial growth more effectively.
Clinical Uses: Trimethoprim is often combined with a sulfonamide (usually sulfamethoxazole) to form co-trimoxazole (TMP-SMX), a potent combination used to treat a variety of infections, including UTIs, respiratory infections, gastrointestinal infections, and Pneumocystis pneumonia.
Combination Therapy: Co-trimoxazole (Trimethoprim-Sulfamethoxazole)
The combination of trimethoprim and sulfamethoxazole is more effective than either drug alone because it blocks two sequential steps in the folic acid synthesis pathway. This dual inhibition reduces the likelihood of bacterial resistance and provides a synergistic effect.
Clinical Importance: Co-trimoxazole is widely used to treat a range of bacterial infections and is also the first-line treatment for Pneumocystis jirovecii pneumonia (PCP) in immunocompromised patients, such as those with HIV/AIDS.
Why Folic Acid Synthesis is a Target
Selective Toxicity: Humans do not synthesize folic acid; instead, we obtain it from our diet. Bacteria must synthesize their own folic acid to survive, making this pathway an excellent target for selective toxicity. This means that antimetabolite antibiotics specifically target bacterial cells without harming human cells.
Measuring antibiotic susceptibility and resistance
antibiotic resistance is defined as a drug concentration that would not be able to treat an infection in the clinical dose
resistance is measured by minimum inhibitory concentration is used, this is the lowest possible concentration you would need in order to kill bacteria or stop it from dividing
turbidity means cloudiness
-lowest conc with no turbidity is the MIC
Measuring antibiotic susceptibility and resistance
tolerance and resistance disc diffusion tests
disc diffusion tests are commonly used in labs to determine the viability of antibiotics
it works by- putting bacteria of interest on an agar plate and you place discs containing small amounts of the antibiotic and when the antibiotic diffuses into the agar it produces zones of various sizes and you can analyse the size of the possible zones to determine whether the bacteria are inhibited or not by the antibiotic
- ff the zone of inhibition is wide then the bacteria are easily inhibited by the antibiotic but if the zone is small or does not exist then the bacteria may be resistant and the antibiotic is not good at inhibiting the bacteria
so these can help determine what is and what is not clinically useful
the cutoff point helps determine what would be useful and what would not be useful
there are different cutoff points for the susceptibility zone to determine sensitive and resistant bacteria
- this is a problem related to the way in which the agar and the antibiotics interact differently as antibiotic molecules are of different sizes, some smaller molecules diffuse more easily through the agar than bigger molecules so the zones are bigger because the antibiotics are spread faster through the agar
There is no linear relationship between MIC and zone
diameter
they extrapolate the zone diameter by knowing what the MIC is when they’ve tested a sample of strains using the MIC serial dilution
-theyre semi-quantitatve because you cannot extrapolate much from the diffusion results other than whether the bacteria is sensitive or resistant
you cannot get any linear relationship between the concentration of the drug and the zone diameter, instead, it is more of an exponential relationship so you cannot extrapolate an intermediate point very easily so you cannot easily figure out the point at which the bacteria becomes sensitive so you’re left with semi-quantitative data
How the Disc Diffusion Test Works
Method: Antibiotic-impregnated discs are placed on an agar plate that has been inoculated with the test bacteria.
Incubation: As the bacteria grow, the antibiotic diffuses out of the disc into the surrounding medium, creating a gradient of antibiotic concentration.
Zone of Inhibition: The effectiveness of the antibiotic is determined by measuring the size of the zone of inhibition, which is the clear area around the disc where bacterial growth has been prevented.
Why It’s Considered Semi-Quantitative
Estimation of Antibiotic Susceptibility:
The test gives a relative measure of how susceptible the bacteria are to the antibiotic by the size of the zone of inhibition. Larger zones generally indicate higher susceptibility, while smaller zones suggest resistance.
However, the test does not provide an exact concentration of the antibiotic needed to inhibit the bacteria, making it an indirect measure of the antibiotic’s effectiveness.
Comparison to Standardized Charts:
The zone of inhibition is compared to standardized charts that categorize the results as susceptible, intermediate, or resistant based on predefined breakpoints.
This classification provides an estimate of the antibiotic’s efficacy but not the precise MIC values required for more detailed dosing information.
Influence of Test Conditions:
Factors such as the rate of antibiotic diffusion, the thickness of the agar, and the bacterial strain’s growth rate can affect the size of the inhibition zone.
These variations mean the test can only offer a semi-quantitative measure rather than an exact quantitative assessment of the antibiotic’s potency.
Limitations and Interpretation
While the disc diffusion test gives a good overview of an antibiotic’s effectiveness, it lacks the precision of tests like the broth dilution test or E-test, which can provide exact MIC values.
The results are best used as a guide to help clinicians decide which antibiotics are likely to be effective, but not to determine the precise concentration required to inhibit bacterial growth.
New and emerging methods for ascertaining resistance
we have well established resistance genes in certain pathogens of interest then some techniques just sidestep this process of disc diffusion and MIC all together And we’ll just have a look at a PCR of a gene of interest that will almost certainly predict whether a class of antibiotics won’t be useful anymore
so again, there’s genes, in the ESPL groups; there’s genes in MRSA, organisms that are highly conserved, and are very accurately detected with these kind of methods with rapid results especially in situations where for example, someone is going to surgery in short notice and you need to know if that person was carrying methicillin resistant Staphylococcus aureus on their skin (MRSA) because if they did then they would need to treat that patient very differently carefully. So to get a more rapid result than that which can be achieved by cultures, They might just put that sample through molecular diagnosis so that they could identify whether the person had that strain
Preserve and conserve what we already have
we would not treat someone with gonorrhoea with penicillin now because the likelihood of resistance is too high, but the drug still has use elsewhere
but also regarding about how to prevent resistance from developing.
one of the strategies is that where you have these old drugs that, are becoming a little less useful for many different diseases, if you could preserve their use where you can, it avoids placing pressure on the alternative antibiotics that may have resistance developing to them at a faster rate
so use up what we can is a general principle whilst reducing the use of antibiotics another more overarching principle
but to extend the effectiveness of antibiotics, without putting pressure on some of the more precious newer class drugs using up what we can is a general principle
Treatment for
Meningococcal disease
Gonococcal disease
the problem with meningococcal diseases is the speed at which they spread by the antibiotic options for the disease are very good
the antibiotic options for gonococcal disease are not as good so dual drug treatments are now recommended this can pose a problem for encouraging antibiotic resistance
however-
why do you think there’s such a big difference regarding Why two species that are so closely related in many respects, are so different in terms of antimicrobial resistance and the options we have available for treatment.
-The drugs have been the drugs for treatment, have gone away, have been much less regulated than the drugs for most other types of infectious diseases.
on the one hand you’ve got a disease that will almost certainly be managed by clinicians in hospital in terms of meningitis and a disease which is more likely to be managed by the patient managing their own drugs at home which means there will be people who will not finish their full course of the drug after starting to feel better meaning they then get residual bacteria that may be slightly more resistant to that drug.
gonorrhoea is a very common disease whilst meningitis is a very rare disease, gonorrhoea is also very stigmantised due to it being an STD so people getting over the counter drugs rather than clinical support so people take them without following correct protocols and so the bacteria has more chance to evolve
The drugs don’t work for gonorrhoea
resistance in the bacteria has been very strong as most drugs have become useless
Urinary tract infection (UTI) – basic overview
Q7. Which bacteria may
cause urinary tract
infections?
what is misunderstood about UTIs is that they are a major cause of sepsis; unmanaged urinary tract infections in vulnerable patient groups are major causes of sepsis because you can get an ascending infection very quickly, where the infection may spread very quickly to the kidney and the kidneys are rich in blood vessels and so as a result of that the infection can spread very quickly into the bloodstream; causing a bloodstream infection
bacteria from the gut can spread to the urethra and affect the bladder so ecoli and gut flora can a common cause
Q7- bacteria that can cause UTIs are e.coli,
-Pseudomonas as they’re related to catheter infections; sometimes when we have people who are in hospital, they may have a particular urological or nephrological
condition such as kidney damage they may have a urinary catheter in place And prevention of, flushing out of the urine may predispose infections.
Aetiological agents of urinary tract infection
-Q7. Which bacteria may cause urinary tract infections?
Treatment guidelines and precautions
Q8. Which antibiotic (from the previous lecture) was discussed in terms of dosing
regimes, for renal patients?
Q8- colistin
IV route is used in order to get a higher dose in place
Treatment guidelines and precautions nitrofurantoin is important
nitrofurantoin- this is an antibiotic that is not useful for most other diseases because it has the property of being really rapidly filtered out of the bloodstream.
So if you have a soft tissue infection or some kind of post-operative surgical infection then the nitrofurantoin will not remain in your bloodstream for long enough to be active. so it seems the drug is not particularly useful but what then happens to the drug after it’s filtered out of the bloodstream is that it ends up in high concentrations in the kidneys and for pouring through into the bladder. So this drug uniquely has the property to accumulate unchanged and unmetabolised, whilst still remaining active against bacteria in the bladder in high concentrations. So it makes an extremely useful drug, for rapidly treating, uncomplicated urinary tract infections.
It has a very broad mechanism of action, Inhibits bacterial ATP synthesis, together with RNA and DNA synthesis;
it has good coverage against all those gram negatives and all those enterobacteriales that may occur in the gut that may occur in the gut and spread to the urinary tract and cause infection
P. aeruginosa survives in
hospital environments:
it is more an environmental pathogen than it is a human pathogen, it is not something like TB that is evolved as a human pathogen it survives very well in water and the general environment And it’s as a result of that, that it’s evolved a lot of natural strategies that keep it resistant to a lot of drugs that we have.
lots of specific modifications are needed for beta-lactam antibiotics to get this organism killed by a reasonable dose of antibiotics
this disease has lots of intrinsic resistance
Pseudomonas aeruginosa – intrinsic resistance
But its baseline existence is that it’s very, very tolerant to all kinds of antimicrobials. and it presents a real challenge to find drugs that can be used to treat it, this is a classic opportunistic organism so its infections can also occur in a range of body sites. It can cause anything from respiratory to ear infections to urinary tract infections to soft tissue infections, So you need antibiotics that can get to each of those sites as well.
generally speaking, there’s a range of different, properties that Pseudomonas has naturally that make it intrinsically resistant. one of those is that it has specialist porin proteins; where equivalent gram negatives would be able to take up antibiotic molecules through these porin proteins. Pseudomonas porin proteins Have variations, which mean the antibiotics can’t go through, So it’s generally very much less permeable than other gram negatives. And if the antibiotic does get in, then it’s usually going to be spat back out again. Because another property of Pseudomonas that make it so resistant is the possession of all of these efflux pumps.
Very good at recognising molecules that don’t belong in there and it has to move back out again. So anything that gets into the cell usually just gets back, back out again.
-And not that it’s depicted on this particular diagram, but Pseudomonas is also very rich in all types of enzymes that break antibiotics down. So it naturally has beta-lactamase which means that presenting it with any antibiotics from that group probably won’t kill it.
so we have a species here which affects very seriously ill patients as an opportunist and is also very, very difficult to kill.
Summary of spectrum of activity of antibiotics
Introduction of antimicrobial agent
Q9. The impact of antimicrobial resistance extends to many areas of healthcare -
can you suggest branches of medicine / types of illness that are impacted?
pathology, infectious disease, Things like cancer chemotherapies, knocking out the immune system, things like organ transplants that are successful because we have antibiotics to keep the infections down whilst people have to take immunosuppressant drugs,
Stepwise proliferation of antimicrobial-tolerant strains can lead to resistance
in terms of where we’re going in terms of where the future is taking us, I think there’s a lot of doomsday predictions about antimicrobial resistance. And they’re very correct. They’re very, accurate. And we should be concerned. We do have a positive however and this occurs with the fact that nearly all infectious diseases are still treatable with antibiotics.
-So we have to keep a bit of a measure on our doomsday predictions about antimicrobials.
We do still have infections that are treatable. There’s not very many that have been completely resistant to all available drugs. But the problem is that, although we know all of these things, the trend of antimicrobial product prescriptions is not changing as quickly as we need it to.
And again, this diagram here is just, a very simple representation to show what’s happening in patient guts.
And if you overuse antibiotics, we wipe out the more sensitive strains and just leave those slightly more tolerant strains behind. and then those are the ones that take over and replicate
what we have is that the consumption of all of these antibiotic drugs is still increasing globally, And the residual antibiotics don’t just get completely metabolised, you know, they’re passed out of sewage water, in pharmaceutical facilities if they’re not managing their biosecurity properly, So unfortunately, we’re seeing higher levels of exposure to antibiotics in the environment, So we know that there are things like Pseudomonas; We know that there are things like E.coli in sewage and things that will be exposed to concentrations of antibiotics.
Broader consequences of antimicrobial resistance
Projected total global antibiotic consumption (billions of DDDs): 2000–2030.
Predicted deaths attributable
to antimicrobial resistance,
compared to other causes of
deaths.
studies show that by 2050, again, if we don’t change what we do diseases and deaths caused by antimicrobial resistance will overcome any other major cause of cause of death; so it’s a really significant problem to consider
overview of the lecture can you answer all these points?
