Antimicrobials 2 Flashcards
Give two examples of how antibiotics target nucleic acid replication
Inhibit DNA replication e.g. Quinolones
Ihibit mRNA synthesis e.g. Rifampicin
How do inhibitors of DNA replication work?
They inhibit DNA replication by primarily targetting key enzymes required for bacterial DNA synthesis, therby preventing cell division and leading to bacterial cell death
What is the mechanism of action for fluoroquinolones?
Inhibit DNA gyrase and topoisomerase IV
These enzymes are crucial for the uninding and supercoiling of DNA during replication and transcription
Blocking these enzymes leads to breaks in bacterial DNA and prevents replication
Give some examples of fluoroquinolones
Ciprofloxacin (gen 2)
Levofloxacin (gen 3)
Moxifloxacin (gen 4)
Zabofloxacin
What is the spectrum of activity for fluoroquinolones
Broad-spectrum antibiotics which are affective against both gram positive and gram negative bacteria
Give some examples of where fluoroquinolones are commonly used as treatment
Bacterial conjunctivitis
Bacterial pneumonia
Tuberculosis
GI infections particularly shigellosis and gastroenteritis
UTIs
Genital infections - used to be main treatment for gonorrhea but we now have high level resistance against this
Give a more indept description of the mechanism of action of the fluoroquinolones
DNA gyrase normally relieves tension during DNA unwind, introducing negative supercoils to keep DNA untangles and properly coiled for efficient replication
by inhibiting DNA gyrase and topoisomerase DNA becomes damages and ROS accumulate
Eventually resulting in bacterial death
*should chat gpt this for exact mechanism of action etc
What is the normal role of DNA gyrase
DNA gyrase normally relieves tension during DNA unwind, introducing negative supercoils to keep DNA untangles and properly coiled for efficient replication
What are some examples other than fluoroquinolones of inhibitors of DNA replication?
Nitroimidazoles
Nitrofurans
Novobiocin
Give an example of a nitroimidazole and what is the mechanism of action of Nitroimidazoles
Example: Metronidazole
MOA: drug undergoes reduction in anaerobic conditions to form reactive oxygen species that cause direct DNA damage, leading to the inhibition of DNA synthesis
What is the spectru of activity for metronidazole, a nitroimidazole?
Effective mainly against anaerobic bacteria and certain protozoa
It is commonly used to treat infections such as bacterial vaginosis (anaerobes), clostridium difficile and protozoal infections likae amoebiasis
Give an example of a nitrofuran and give its mechanism of action
Example: Nitrofurantoin
MOA: the drug is reduced in bacterial cells to reactive intermediates that damage DNA and inhibit DNA replication
What is the spectrum of activity for a Nitrofuran such as Nitrofurantoin
Primarily used for urinary tract infections caused by E. Coli or other common uropathogens (nitro disc was used for E.Coli and ents)
What is the mechanism of action of novobiocin?
Novobiocin targets DNA gyrase (specifically the GyrB subunit)
It prevents the supercoiling necessary for replication
How is novobiocin used?
Less commonly used now in clinical settings
Was used to treat S. aureus infections and as a research tool in laborator studies
How do inhibitors of mRNA synthesis work?
These antibiotics work by inhibiting bacterial mNA synthesis (through binging to DNA polymerase?)
Essentially blocking the process by which DNA instructions are transcribed into messenger RNA (mRNA)
Give some examples of inhibitiors of mRNA synthesis
Rifampicin
Rifaximin
Rifapentine
What is the mechanism of action of rifampicin?
Binds to bacterial RNA polymerase enzyme
Preventing enzyme from initiating the transcription of DNA into mRNA
This stops the production of essential proteins, ultimately leading to bacterial cell death
It is highly specific for bacterial polymerase making it a highly selective bactericidal agent hence its use in long term treatment e.g. TB or leprosy
What infections is rifampicin used for?
Tuberculosis and leprosy (long term treatment of about 6 months etc)
MRSA infections
Prophylaxis for close contacts of meningococcal and Haemophilus meningitis
What spectrum of activity does rifampicin have?
Effective against gram-positive bacteria, mycobacterium tuberculosis, and some gram-negative bacteria
How do antibiotics Targeting Protein Synthesis work, when are they used?
They inhibit (or knock out) the bacterial ribosome which is the cellular machinery responsible for translating mRNa into proteins
Some of these agents have restricted use due to toxicity concerns
One of the few classes of antimiccorbials where new drugs have been developed - new ribosome - targeting antibiotics have shown practical succss in clinical use
List some common examples of antibiotics taregting protein synthesis
Aminoglycosides
Tetracyclines
Macrolides
Lincosamides
Chloramphenicol
Oxazolidinones
Streptogramins
In general what is the mode of action of antibiotics targeting protein synthesis
They bind to bacterial ribosome at either 30S or 50S
This stops the ribosome from binding to mRNA to form amino acid chains (30S) or elongate the chains to form proteins (50S)
Disruptive effect on many essential bacterial functions leading to cell death
How do aminoglycosides work and give an example of one?
Bind to 30S and cause the misreading of mRNA
e.g. Gentamicin
How do tetracyclines work and give an example of one?
Bind to 30S and block tRNA attachment
e.g. Doxycycline
How do macrolides work and give an example of one?
They bind to the 50S subunit and prevent translocation
e,g, azithromycin
How do lincosamides work and give an example of one?
They bind to the 50S subunit and inhibit elongation
e.g. Clindamycin
How does Chloramphenicol work?
Inhibits peptidyl transferase at 50S subunit
How does oxazolidinones work and give an example of one?
Prevent initiation complex at 50S e.g. linezolid
One of our newer classes
How do streptogramins work
Bind to 50S and disrupt elongation and release peptides
List the antibiotics that act on the 30S
Aminoglycosides
Tetracyclines
List the antibiotics that act on the 50S
Macrolides
Lincosamides
Chloramphenicol
Oxazolidinones
Streptogramins
In your own words how does 30S binding differ from 50S binding
30S binding (to mRNA) prevents amino acid chains being produced and from coming together
50S binding prevents elongation of chains
Talk about aminoglycosides, what are they used for
Antibiotics that work by targeting protein synthesis at the 30S ribosomal subunit, which is different from how most other antibiotics work -> this makes them especially effective for certain multi-drug resistant infections
They are known for their effectiveness in treating severe bacterial infections, primarily gram-negative bacteria
List some of the aminoglycosides and give the infection they are mostly used for
Gentamicin - widely used for various systemic infections
Amikacin - bacteria resistant to other aminoglycosides such as gentamicin
Tobramycin - pseudomonas aeruginosa infections
Streptomycin - originally for TB but now used for TB in combination therapy only due to resistance
Neomycin - topical and sometimes oral for gut decontamination
What is the mechanism of action of aminoglycosides
Binds to 30S ribosomal subunit of bacterial ribosomes
This binding disrupts protein synthesis by causing the misreading of mRNA
Incorrect or defective proteins are produced, leading to cell dysfunction and ultimately cell death
Causes misreading of messenger RNA resulting in defective or incorrect amion acids and therefore proteins that can no longer function
Bactericidial effect
Talk about aminoglycosides foor gram-negative bacteria
Aminoglycosides are used to treat serious infections usch as sepsis, hospital-acquired pneumonia and urinary tract infections
i.e. pathogens such as E. coli, Klebsiela species and Pseudomonas aeruginosa
Talk about aminoglycosides for gram positive infections
Often used in combination with a beta-lactam antibiotic or vancomycin,
When used in this way aminoglycosides can be effective against gram-positive bacteria including staph aureus
Talk about aminoglycosides for tuberculosis
Streptomycin was originally made for TB but resistance emerged so its now only used as part of combination therapy
What kind of side effects do aminoglycosides have?
Ototoxicity (hearing loss, vestibular damage)
Nephrotoxicity
Talk about the ototoxicity affects of aminoglycosides
Hearing loss:
- they can accumulate in the inner ear, leading to hearing loss, which may be irreversible
Vestibular damage:
- balance issue due to damage to vestibular apparatus
Talk about the nephrotoxic effects of aminoglycosides
Known for their potential to cause acute kidney injury due to accumulation of antibiotic in the renal cortex
Risks are higher in patiemts with pre-existing renal issues or those who are dehydrated
How do we monitor for toxicity of aminoglycosides
Monitor for early hearing loss symptoms is essential to mimise long-term damage
Regular monitoring of renal function e.g. serum creatinine levels is crucial to detect early signs of nephrotoxicity
Therapeutic drug monitoring is generally performed in clinical chemistry
- careful monitoring of drug levels in the blood (both peak and trough) is needed to avoid toxicity while ensuring efficacy
Talk about tetracyclines, how are they used
A class of broad-spectrum antibiotics antibiotics
Effective against a variety of gram-positive and gram-negative bacteria, as well as some atypical organism
They were first discovered in the 1940s but they quickly became popular due to their versatility
Commonly used for respiratory infections, acne and atypical bacteria
Give some examples of tetracyclines and what they are used for
Tetracycline: the original drug in this class
Doxycline: known for fewer side effects and good bioavailability
Minocycline: sometimes used for acne due to its anti-inflammatory properties
Tigecycline: a glycylcycline -> derived from tetracycline -> a new antibiotic -> used for resistant bacteria
What is the mechanism of action of tetracyclines?
Target protein synthesis
Bind to 30S ribosomal subunit of the bacterial ribosome
This prevents binding of tRNA which is necessary for adding amino acids to the growing protein chain
As a result protein synthesis is inhibited and thus bacterial growth is prevented
Bacteriostatic and not bacteriocidal
List the clinical uses of tetracyclines
Broad-spectrum activity
Atypical pathogens
Specific infections
Talk about the broad-spectrum activity of tetracyclines
Effective against a range of Gram-positive and gram-negative bacteria, including staphylococcus, streptococcus, E. coli and Klebsiella
Talk about tetracyclines for atypical pathogens
Useful for atypical infections caused by organisms like:
- Chlamydia
- Mycoplasma (dad had this)
- Rickettsia (dad had this)
- Borrelia burgdorferi (Lyme)
Give some examples of where tetracyclines can be used for specific infections
Respiratory tract infections such as pneumonia caused by Mycoplasma pneumoniae
Tick-borne diseases e.g. Doxycycline for Lyme disease (drug of choice)
Doxycycline prophylaxis for malaria
Tetracyclines frequently used in dermatology for acne vulgaris due to its anti-inflammatory properties
What are some of the side effects of tetracyclines?
Gastrointestinal disturbances as with all antibiotics
Photosensitivity can cause increased sensitivity to sunlight, leading to sunburns -> think of dad in sun -> patients advised to use sunscreen or avoid prolonged sun exposure
Tooth discolorisation - can bind to calcium leading to yellow or brown discoloration of teeth in children under 8 years or pregnant women -> used to treat whooping cough hence why some adults have these now
Hepatotoxicity -> at high doses can cause liver toxicity especially in pregnant women or patients with pre-existing liver conditions
Why do we tend to limit the use of tetracyclines
Due to toxicity especially in pregnant women or young children
Increasing bacterial resistance limit use -> hence new drugs like tigecycline important in combating resistance
Talk about glycyclines
A new generation of antibiotics derived from tetracyclines
Developed in response to increasing resistance to older tetracyclines
Designed to combat MDROs such as MRSA and VRE
Broad spectrum effective against gram +/ves, -/ves and atypicals
What was the first glycyclcyclines?
Tigecycline
Approveed by FDA in 2005
How do glycylcyclines differ from tetracyclines
Chemical modification
Structurally similar but with modifications that provide better binding to bacterial ribosomes and enhanced resistance to bacterial defense mechanisms
What is the mechanism of action of glycylcyclines
Target protein synthesis
Bind to 30S ribosomal subunit
Prevent tRNA from binding to the ribosome, blocking the addition of amino acids to the growing protein chain
Result in inhibition of bacterial protein synthesis thus bacteriostatic like tetracyclines
What is the spectrum of activity of glycylcylines
Gram positive bacteria
Gram negative bacteria
Anaerobic and atypical pathogens
Talk about glycylcyclines for gram positives
Effective against resistant strains like MRSA and VRE
Talk about glycylcyclines for gram negatives
Broad activity
ESBL producing Enterobacteriaceae and A. baumannii (baumannii tends to be very resistant but these are effetive against it)
Limited use against PA
Talk about glycylcyclines for anaerobes and atypicals
Activity against clostridium species, mycoplasma pneumoniae, legionella and chlamydia
What are the three main advantages of glycylcyclines
Address common tetracycline resistance mechanisms such as efflux pumps and ribosomal protection
Broad spectrum activity including MDR GPs and GNs
Effective for mixed infections involving multiple pathogens
How do glycylcyclines overcome efflux pumps?
Structural modifications make tigecycline resistant to bacterial efflux pumps, which often render tetracyclines ineffective
How do glycylcyclines overcome ribosomal protection?
Structural changes allow for stronger binding to ribosomes even in resistance strains
Talk about oxazolidinones
These are the first in a new class of bacterial protein synthesis inhibitors
They have broad activity against gram-positive cocci, including MRSA and VRE
Resistance is rare
Give two examples of oxazolidinones
Linezolid
Tedizolid
How does linezolid work
Targets 23S rRNA within the 50S ribosomal subunit
It prevents the formation of a functional 70S initiation complex, thereby inhibiting protein synthesis
Talk about Tedizolid and its uses
A newer oxazolidinone - an improved version of linezolid
Has extended activity compared to linezolid
It has improved pharmacokinetcs and fewer gastrointestinal side effects then linezolid
Why is resistance rare against oxazolidinones?
Due to its unique mechanism of binding to 70S
This makes oxazolidinones highly effective even against resistant gram positives
Antibiotics that are active against cell wall membranes work in what three different ways?
Those that disrupt the membrane structure
Those that alter membrane permeability
Those that affect membrane enzyme systems
What antibiotics disrupt the cell wall membrane structure?
Pomyxins such as colistin
Polyenes such as amphotericin B or Nystatin
Newer agents such as lipopetides like Daptomycin
Give an example of a polymyxin
Colistin
Give two examples of polyenes
Amphotericin B
Nyastatin
What kind of antibiotic is daptomycin
A lipopeptide
Give an example of an antibiotic which alters membrane permeability
Gramicidins
How do gramicidins work?
They disrupt the bacerial cell wall integrity, increasing permeability
Give an example of an antibiotic that affects membrane enzyme systems
Antimycin
How does antimycin work?
It interferes with membrane-associated enzymatic processes
What is the spectrum of activity for colistin or polymyxin E
Theyre effective primarily against multi-drug resistant gram negative bacteria including Pseudomonas aeruginosa, Acinetobacter baumanii and K. pneumoniae
They were initially used wiely but use has declined due to toxicity however usage resurgence as a last-resort antibiotic due to increasing resistance
What is the mechanism of action for colistin or polymyxin E?
They act on the bacterial cell membrane - bactericidal
They bind to LPS on the outer membrane of gram negative bacteria
They displace calcium and magnesium ions, leading to membrane destabilisation
This causes permeabilisation of the membrane, leading to leakage of intracellula contents and cell death
What are some of the clinical indications for the use of colistin?
Pneumonia - hospital acquired or ventilator-associated
BSIs caused by MDR gram-negatives
UTIs especailly those caused by resistant strains
Nebulized formulation used in combination with other drugs to treat P. aeruginosa biofilm infection in CF
What are the two main toxic effects of colistin?
Nephrotoxicity
Neurotoxicity
Talk about the nephrotoicity of colistin
Can cause acute kidney injury especially with prolonged use
Requires close monitoring of renal function during therapy
Talk about the neurotoxicity of colistin
May cause symptoms like dizziness, muscle weakness and neuromuscular blockade
In rare cases it may lead to respiratory paralysis
When is colistin consiered a last-resort antibiotic?
Its often a last-resort ‘emergency antibiotic for MDR/CRE K. pneumo, P. aeruginosa and Acinetobacter
What are polyenes?
A class of antifungal agents including amphotericin B (Fungizone and Nyastatin)
What is the mechanism of action of polyenes?
Highly lipophilic -> they combine with membrane sterols, particularly ergosterol found in fungal cell membranes
Membrane disruption -> binding disrupts membrane structure and creates pores which leads to leakage of K+ ions and other essential cell components
What is the spectrum of activity of polyenes?
Active against fungal, algal and protozan cells
Commonly used for the treatment of systemic fungal infections
What is daptomycin, what is its spectrum of activity?
Dapto is a cyclic lipopeptide
It is used for gram-positive bacterial infections, partiularly effective against MRSA
Why is daptomycin particularly useful in MRSA
Daptomycin reduces the expression of mecA in MRSa which is a key gene conferring methicillin resistance
NB no affect on mecC
What is the mechanism of action of daptomycin?
Lipophilic Tail: binds to the cytoplasmic membrane of bacteria
Membrane permeabilisation: targets liposomes containing phosphatidylglycerol
This combination causes potassium efflux leading to membrane disruption and cell death
How is daptomcin selective
It only targets liposomes containing phosphatidylglycerol which is abundant in bacterm CM but not human CM
What spectrum of activity does daptomycin have?
Effective against gram-positive bacteria
Especially MRSA and VRE
Daptomycin is only approved for specific uses, what are these?
Complicated Skin and Skin Structure Infections (CSSSI) -> MRSA, MSSA, Streptococus sp and enterococcus spp
Bacteremia and Endocarditis -> S. aureus BSI or Right-sided endocarditis (staph endocarditis)
Alternative to Vancomycin -> for those who are allergic or non responsive to vanc
Renal dysfunction where other therapies would be ess favourable like polymyxins
What are competitive inhibitors also called?
Anti-metabolites
What are competitive inhibitors? How do they work?
Antibiotics that inhibit bacterial metabolic pathways
Several antimicrobials inhibit bacteria metabolic processes
These agents act as structual analogues competing for active enzyme sites and thus blocking production
Give two examples of classes of competitive inhibitors
Sulfonamides
Trimethoprim
Talk about sulfonamides
They inhibit folate synthesis
They comete with PABA a precursor in folate synthesis, blocking dihydrofolic acid formation
Talk about trimethoprim
They inhibit folate metabolism
By inhibiting dihydrofolate reductase, blocking tetrahydrofolate formation, which is crucial for DNA synthesis
What does PABA stand for?
Para-aminobenoic acid
What are the four main challenges in antibiotic development
Drying pipeline: theres currently o production pipeline - were going to face a ‘post-antibiotic era’
Theres only 5-20 novel drugs in clinical development but progress is very slow and expensive taking abou 15 years and over 800 million
Economics are broken -> leading to few new classes reaching phase III trials -> focus on making other drugs where resistance isnt an issue
Focus on gram positives -> new drugs like linezolid mainly target gram positives -> no drugs to keep up with gram negative resistance
Talk about advancements in extending existing antibiotics
Fifth generation cephalosporins in development
New inhibitors such as avibactam and varobactam with extended activity of existing agents
List some fifth-generation cephalosporins
Dalavancin
Ceftobiprole
Plazomicin
Solithromycin
Give two examples of new inhibitors
Avibactam
Varobactam
What are our novel antibiotics
Glycylcylines such as Eravacylcine
Oxazolidinones such as Tedizolid
Cyclic lipoptides such as daptomycin
What are the three new methods of treating bacteria being looked at
Target specific pathogenesis e.g. inhibiting critical steps in the pathogen lifecycle
Disrupt pathogen maintenance e.g. lowers risk of inducin resistance
Resident microorganisms safe -> less likely to impact beneficial microbes (think C. diff)
Give two examples of precision antimicrobials
Targetting biofilm
Taregtting UPEC binding
Talk about targetting biofilms
Prevent biofilm formation through signalling pathway inhibition or biofilm breakdown using enzymes
Talk about UPEC binding
Use of mannosides to block FimH adhesion in UTIs without affecting gut flora
What are the 6 new antimicrobial strategies
Cellular pathways
Efflux pump inhibitors
Metallic nanoparticles
Immune-based therapies
Faecal microbiota transplant
Talk about looking at cellular pathways as a new antimicrobial strategy, give an example
Looking for new metabolic targets
Targets central to metabolic pathways e.g. bedaquilline targets ATP synthase in TB
Talk about eflux pump inhibitors as a new antimicrobial strategy, give an example
Reverse MDR phenotypes -> make resistant bacteria more resistant
Phophorbide A inhibits NorA in S. aureus and MexAB-OprM in P. aeruginosa
Talk about metallic nanoparticles as a new antimicrobial strategy
Interact with negatively charged surfaces causing membrane disruption
Reactive oxygen species are then generation and metal ions are released
However toxicity is an issue and they tend to impact microbiomes thus limiting their clinical applications
Give an example of an immune based therapy as a new antimicrobial strategy
MAB directed against P. aeruginosa LPS
Talk about Faecal micorbiota transplant as a new antimicrobial strategy
Used to restore gut resistance to MDR enteric pathogens
-> C. diff
Talk about Faecal micorbiota transplant as a new antimicrobial strategy
Used to restore gut resistance to MDR enteric pathogens
-> C. diff
Talk about Faecal micorbiota transplant as a new antimicrobial strategy
Used to restore gut resistance to MDR enteric pathogens
-> C. diff
