Lecture #11 - Antimicrobial Drugs & Drug Resistance Flashcards
Antimicrobial Drugs are used…
Used when immunization has not occurred (no successful vaccine) and the immune system has difficulty to eliminate infection (ex: HIV)
• Useful against bacterial infection (antibiotics), very few antivirals (used for viral infection) are available (& those avail. are so restricted/limited)
Antimicrobial Drugs
These are compounds that…
kill (cidal/lytic) or control the growth (static) of microorganisms in the host
• These drugs MUST display SELECTIVE TOXICITY or they will cause damage to the host
- b/c an antibiotic not used topically, is being let loose in body (full access to tissues) - ensure it won’t do non-specific tissue damage
Antimicrobial Drugs
Two broad categories
SYNTHETIC (mostly failed - b/c have to design drug that has appro. polarity, size characteristics, no natural transporters exist, therefore, challenging & has to get to min. inhibitory [ ] in tissue (bone, or nervous tissue for ex which is diff) AND NATURAL (out #)
• Large number of naturally occurring antibiotics with no clinical use
- (naturally) Produced by bacteria and fungi (penicillium or straphylosporium for ex)
Antimicrobial Drugs
Can also be described based on whether they are:
• Bacteriostatic or bacteriocidal
• Broad spectrum or narrow spectrum
- broad could be: target all gram + & gram - (broad over 1 that only targets gram -), BUT can also be broad if target all gram - (vs. 1 that targets just E. coli)
Antibiotic targets include:
Cell wall synthesis
can target cell wall with diff categories of antibiotics & it’ll be impacted
Antibiotic targets include:
Targets for nucleic acid syn.
capacity to interfere with DNA replication or prod. of RNA transcripts (intermediates b/t DNA & protein)
Antibiotic targets include:
Protein syn.
can interfere with ribosomes –> protein syn.
- prevent bact from syn proteins needed for cell function
Antibiotic targets include:
Lipid biosyn.
target anabolic pathways to be able to build things like lipid which is necessary for mem’s; esp. bact. cells b/c don’t have mem. bound organelles (internal mem’s will be impacted)
Antibiotic targets include:
Cytoplasmic membrane structure & function
anything that targets cytoplasmic mem, mostly has:
TOXICITY TO US –> NOT AS WIDELY USED
- b/c our PM as Euk cells & their PM as a prok. cell are comparable to 1 another which means not something you can easily target without causing harm to your cell
Antibiotic targets include:
Folic acid metabolism
can inhibit pathways for metabolic syn
–> turn down folic acid syn
Cell Wall Active Antimicrobial Drugs
Cell wall active agents offer EXCELLENT SELECTIVE TOXICITY • MOST WIDELY USED class of antibiotics
- no harm to OUR own cell b/c we lack PD, therefore don’t target anything we have apart of our cell
- but can dev. allergy if it complexes with proteins in our blood for ex, behaving like a hapten & manages to get attention of immune system (not common)
Cell Wall Active Antimicrobial Drugs
Largest class are…
beta lactam antibiotics
Cell Wall Active Antimicrobial Drugs
Largest class are beta lactam antibiotics
• Common feature is the b-lactam ring
- core for all this category of antibiotic (can be dressed up with diff functional groups –> will determine where drug could go & conseq. for inside of cell & what the targets will be & how will it be given (orally or IV)
• NATURALLY occurring: produced by Penicillium and Cephalosporium fungi
- found as products of microbial metabolism
- each produce diff. categories of B-lactam; *all have ring but dressed up differently
• Example: penicillins and cephalosporins
• Can be MODIFIED in the lab to produce SEMI-SYNTHETIC drugs that have a modified spectrum of activity
- Reason for this: to change spectrum of activity; give it more activity against a gram - or gram +, more activity against a partic. species of bact.
• Susceptible to beta-lactamases
- Enzyme produced by some bugs to cut and inactivate beta-lactams (drug no longer works - good for bact but not for us)
- THEREFORE, B-lactamase is a FORM OF ANTIBIOTIC RESISTANCE
Cell Wall Active Antimicrobial Drugs
Penicillins
Penicillins have a NARROW spectrum of activity
- prod. by penicillum mold (natural)
• Characterized by a FIVE membered ring (thiazolidine) attached to the beta-lactam component
*• Target TRANSPEPTIDATION in GRAM POSITIVE bacteria
• CANNOT PENETRATE outer membrane of GRAM NEGATIVE bacteria (don’t work against gram -)
- SEMI-SYNTHETIC penicillin are modified to provide SOME ACTIVITY AGAINST gram NEGATIVE bugs
- Example: ampicillin
*(can’t predict these sorts of things, so have to test antimicrobial in lab to see if these drugs will work against gram +/- experimentally)
Explain how Penicillins target transpeptidation in gram +’s
transpeptidation: creates perpendicular cross-links using peptide chains
penicillin drug binds to transpeptidase (enzyme respon. for formation of cross-links)
outcome: WEAK CELL WALL
- when H20 rushes into hypertonic envir. of cell, it’ll cause cell to rupture –> bact no longer viable
Explain Ampicillin (ex of penicilin)
broadened spectrum of activity (esp. against gram -), acid-stable (maintain acid sensitivity), B-lactamase-sensitive (means B-lactam will be destroyed by B-lactamase if organism has that)
Not all penicillins will be…
susceptible to B-lactamase enzymes
Cell Wall Active Antimicrobial Drugs
Cephalosporins
• Structurally distinct from penicillins (despite sharing B-lactam ring)
- SIX membered ring is attached to the beta-lactam component
- Also target transpeptidation of peptidoglycan (like penicillin)
- Many semi-synthetic examples (enhance activity & increase spectrum of activity etc.)
- BROADER SPECTRUM of activity than penicillin (cast wider net –> target more than penicillin can target)
- BETTER RESISTANCE against beta lactamases (harder for B-lactamase enzyme to activate & cut same B-lactam ring the penicillum’s had b/c less accessible due to change of chem)
- Grouped into GENERATIONS
- 1st generation cephalosporin, 2nd generation cephalosporin etc.
- each gen. will have its own characteristic target & outcome - what its able to go after (gen categories play role in est. & understanding what the function of category will be)
- all have cepha as route –> cepha - beginning of each antibiotic
- associate ending with what gen it belongs to & will then associate that with which gen will work against gram -‘s better etc. to choose best for situation
Compare & constrast Penicillins & Cephalosporins briefly
biochem of drugs are diff (6-mem ring vs 5 mem ring), process it targets is same (both target transpeptidation)
Growth Factor Analogs
Growth factor analogs (drugs) are structurally similar to growth factors but do not function (behave) in the cell
• Analogs similar (resemble) to vitamins, amino acids, and other compounds (necessary in process)
Growth Factor Analogs
Example: Sulfa drugs
FULL SYNTHETIC category (man-made)
- recently quite lost efficiency –> don’t use them to same degree as before
- even when might be useful, they have a *lot of resistance (organism may have resistance to drug)
• Discovered by Gerhard Domagk in the 1930s
- Example: sulfanilamide
• Inhibit growth of bacteria by INHIBITING FOLIC ACID SYNTHESIS and thus NUCLEIC ACID SYNTHESIS
- needed for syn of nitrogenous bases; to be able to assemble in bact cell, things like purines & pyrimides & also in biosyn. of some AA’s as well
- BACT has a biosyn pathway that does this - BUT for humans we get folic acid from our diet to satisfy req’s, therefore safe for us (no issue with toxicity b/c of that –> PERFECT SELECTIVE TOXICITY)
• Often used in COMBINATION with another analog –> TRIMETHOPRIM
- Combination therapy MINIMIZES the LIKELIHOOD of RESISTANCE
Describe how Sulfa drugs (ex: sulfanilamide) is carried out as well as how it is in combo with another analog (trimethoprim)
- enzyme necessary in process to make folic acid will be tricked into using sulfa drug instead
- outcome: not folic acid (drug analog is in here) –> problem
- manipulates enzyme to choose to use drug instead of its natural substrate (sulfa drug used in place of PABA)
*trimethoprim is a sub. for other part (now, not only tricking enzyme to take Sulfa drug instead of substrate (called PABA), you also use trimethoprim in for other part & now folic acid is rly not folic acid b/c used 2 substrates that look same but aren’t same (combo = TMP-SMZ) which *decreases likelihood of resistance b/c using 2 things bombarding organism so it doesn’t have capacity to est. resistance to it
Growth Factor Analogs
Example: Isoniazid
• EXTREMELY NARROW SPECTRUM cell wall active agent
- b/c targeting mycolic acid syn (1 species)
• ANALOG of MYCOLIC ACID component needed by Mycobacterium spp. (only affected)
Nucleic Acid Synthesis Inhibitors
Quinolones
- SYNTHETIC antimicrobials (man-made)
- INHIBIT DNA GYRASE
- Prevents supercoiling of DNA (& has packaging issue with respect to cell size)
- b/c cells so small, you have to supercoil to fit all that DNA into interior compartment of prok. cell
- -PROKARYOTIC ENZYME (WE DON’T HAVE/USE IT - SELECTIVE TOXICITY IS GOOD)
• Active against BOTH Gram-negative and Gram-positive bacteria (BROAD SPECTRUM)
Nucleic Acid Synthesis Inhibitors
Quinolones
Example:
Example: ciprofloxacin (big gun) a fluorinated quinolone (fluoroquinolone)
• Useful AGAINST LIFE THREATENING INFECTIONS
- drug will be somewhat aggressive but good at what it does
- ex: complex chest infection
- ex: complicated UTI
Nucleic Acid Synthesis Inhibitors
Quinolones
Example: ciprofloxacin a fluorinated quinolone (fluoroquinolone)
PROBLEM:
INTERFERES WITH CARTILAGE DEV.
- if any chance woman is PREGNANT, you CAN’T give them cipro - b/c entire fetal skeleton is gonna be laid down 1st as cartilage & then necessary sections meant to become bone will complete ossification process & then parts of skeletal system aren’t meant to ossify will stay as carriage (ex: nostrils)
Nucleic Acid Synthesis Inhibitors
Quinolones
Rifampin:
binds to RNA polymerase preventing transcription
Outcome: RNA polymerase = inactive
Nucleic Acid Synthesis Inhibitors
Quinolones
Actinomycin:
Binds to DNA template blocking transcription elongation
- RNA polymerase can’t get on & assemble nucleotides
Protein Synthesis Inhibitors
target process of translation!
Protein synthesis inhibitors target 70S ribosomes
• GOOD SELECTIVE TOXICITY (but not perfect)
• SOME ISSUES because human cells have 70S ribosomes in the mitochondrial matrix
- kidney’s suffer biggest conseq’s
Protein Synthesis Inhibitors
Include:
Aminoglycosides
Tetracycline
Macrolides
Protein Synthesis Inhibitors
Include:
• Aminoglycosides
• Bind to the 30S subunit (SSU) of 70S ribosomes
*• BLOCK TRANSLATION - ability to syn proteins (which are necessary workhorse of cell) are comprimised
• NARROW SPECTRUM (no gram + coverage)
- Useful AGAINST GRAM NEGATIVE bugs
- (only know if you try experimentally)
• Often used as a last resort drug
b/c
• Damaging to the kidneys (nephrotoxicity) and ears (issues with hearing & balance)
• Examples include streptomycin, gentamycin and neomycin
Protein Synthesis Inhibitors
Aminoglycosides
Examples include:
streptomycin, gentamycin and neomycin
Protein Synthesis Inhibitors
Tetracycline:
- BROAD SPECTRUM
- Produced by species of the Streptomyces genus
- Bind to the 30S subunit (SSU) - diff. interaction than aminoglycosides
- Consist of BOTH natural and modified semisynthetic drugs (& more resis –> capacity to handle other things b/c of modifications that made them more resilient)
• BINDS to CALCIUM (removing it from solution, therefore not enough in ECF for things like n.t. exocytosis in NS, cardiac muscle contraction) damaging TEETH and BONE
- SHOULDN’T be used in CHILDREN and PREGNANT
WOMEN
–> these individuals are actively assembling bone; actively undergoing ossification, therefore need for Ca2+ is much higher than normal
• Used in VETERINARY MEDICINE and to promote animal growth
- Creates PROBLEMS WITH RESISTANCE
- antibiotics can provide diff. attributes of protection
- problem: exposing bacteria unnecessarily to antibiotics which can allow them the opp. to dev. resistance & we can also be exposed to it (can be found in trace amounts in drinking water)
For Protein Synthesis Inhibitor - Tetracycline
Why would using an antibiotic on a farm animal be associated with the promotion of growth?
kills off normal flora –> means organisms competing for nutrients will be inhibited
animals’s healthy = can sell meat
animal’s have bacterial infection = not safe to sell meat
Protein Synthesis Inhibitors
Macrolides
• Broad spectrum of activity
- • Bind to the 50S (LSU) ribosomal subunit
- when it binds to LSU, organism has some capacity to translate protein but it’ll be reduced –> call it a type of PREFERENTIAL TRANSLATION (translate based on imp./priority now)
- Only inhibits translation of some proteins
- Some proteins are preferential translated and others are not
- Creates a DETRIMENTAL PROTEIN IMBALANCE inside of the cell (high levels of some protein & low levels of others - detrimental to survival of bact cell)
• Useful to treat infection in patients with allergies to beta lactam antibiotics
Protein Synthesis Inhibitors
Macrolides
Example:
erythromycin and azithromycin (naturally occuring)
• Produced by Streptomyces spp.
Novel Antibiotics (last ~10 years)
Daptomycin
- Produced by Streptomyces spp.
- Cyclic lipopeptide
- Active AGAINST Gram-POSITIVES
- Pathogenic Staphylococcal spp. and Streptococcal spp. (strep throat, flesh eating disease etc.)
- now got backup if vancomycin fails
• Forms pores in the plasma membrane causing DEPOLARIZATION (more + in cell)
- Cell cannot synthesize necessary biomolecules (like protein, RNA, etc.)
- Cell death occurs
• RESISTANCE can occur when bacteria alter plasma membrane composition
- effective mode to protect organism
Methicillin
= penicillin that’s SEMI-SYNTHETIC with MODIFICATIONS to make it RESISTANT to B-lactamase activity (blocks B-lactamase site to cut)
MRSA (resistant to our answer (war b/t us & them)
methicillin-R
staph aureus (up until recently, only drug to treat MRSA)
Vancomycin was last resort for it (if immune system didn’t work against it, you’d die)
Novel Antibiotics
Platensimycin
- INHIBITS FATTY ACID BIOSYNTHESIS (inhibits ANABOLISM)
- Produced by Streptomyces platensis (hot genus for antibiotic prod. (we like it)
• BROAD spectrum of activity against gram POSITIVE bacteria
- broad spectrum compared to Isoniazid for ex
• Useful AGAINST important RESISTANT gram POSITIVE PATHOGENS
- MRSA and VRE - *vancomycin - resistant (resis. to our answer to MRSA)
- Entercocci (enterococcal species are normal flora in our GI tract)
- if you’ve picked up resis. to vancomycin & then MRSA enters into your body:
- VRE gives MRSA some vancomycin resistance, so the MRSA will not only be resis. to mycocyin but also vancomycin
- therefore exchange of genetic material that they do freely will create serious repercussions to us
- having this drug to be able to target those guys is awesome
• Does NOT CAUSE TOXICITY in the HOST
- safe to use inside us, despite targeting FA anabolism
Antibiotic Resistance
Antibiotic resistance occurs when an organism develops a mechanism to elude the activity of an antimicrobial drug that it should otherwise be susceptible to
• Genes for antibiotic resistance can either be encoded on a PLASMID (*passed by conjugation - horizontal gene transfer) or directly within the CHROMOSOME
Antibiotic Resistance
Resistance is prevalent because of
widespread and sometimes incorrect use of antibiotics (can’t let immune system do job if it can, otherwise seek antibiotics)
– Medicine, veterinary medicine, agriculture
Antibiotic Resistance Mechanism’s:
- Reduced permeability
- Inactivation of antibiotic
- Alteration of target
- Development of resistant biochemical pathway
- Efflux
Antibiotic Resistance
Mechanism: Reduced permeability
- SPECIFIC
Ex: not opening house to someone scary (reducing permeability to something that could cause harm)
- sees antibiotic, understands it could be harmful to cell structure/survival so it reduces permeability & choses not to let antibiotic drug into cell
Ex: Penicillins
Antibiotic Resistance
Mechanism: Inactivation of antibiotic
- SPECIFIC
- B lactamase (inactivation by cutting B-lactam ring so no longer effective to interfere with transpeptidase of PD layer)
Ex: Penicillins, chloramphenicol, aminoglycosides
Antibiotic Resistance
Mechanism: Alteration of target
- SPECIFIC - b/c just 1 int. won’t be possible
- antibiotic won’t be able to bind the target (antibiotic ineffective) b/c of a modification (mutated away from antibiotic so its able to persist - replicate; repro. success & see larger #’s within pop.)
Ex: Erythromycin, streptomycin, norfloxacin
Antibiotic Resistance
Mechanism: Development of resistant biochemical pathway
- SPECIFIC
enzymes used in biochemical pathway, for ex: folic acid syn, maybe able to avoid effects of antibiotic - structure in pathway won’t be targeted by antibiotic & still continue to happen despite antibiotic being there
Ex: Sulfonamides
- lot of resistance to Sulfa drugs (target metabolic pathways)
- this a mech that those bact use to avoid sulfa drug elimination
Antibiotic Resistance
Mechanism: Efflux
let things in, & then open door (efflux pump) & let them out
pump in mem.
- CAUSES MDR: multi-drug resistance - any drug that’ll fit through pump is gonna be ejected; provide resis. to a series of antibiotics
ex: Tetracyclines, chloramphenicol, fluoroquinolones
Which Antibiotic Resistance mechanisms are VERY SPECIFIC TO A CERTAIN ANTIBIOTIC (resis to that 1 but doesn’t provide protection to others)?
- Reduced permeability
- Inactivation of antibiotic
- Alternation of target
- Development of resistant biochemical pathway
Which Antibiotic Resistance mechanisms CAUSES MDR: multi-drug resistance (any drug that’ll fit through pump is gonna be ejected; provide resis. to a series of antibiotics)?
Efflux
ex: Tetracyclines, chloramphenicol, fluoroquinolones
Patterns of Antibiotic Resistance
• Emergence of antibiotic resistance in different species of bacteria
- MORE we use drugs, MORE we expose bact to them, MORE likely they’re to dev. resis.
- game of exposure; if you expose them, the opp. to be able to cause probs will be greater b/c bact needs to see the drug to be able to figure a way around it
- happens as conseq of spon. mutation, but if mutations are successful the organism is able to stick around
• Patterns of antimicrobial resistance
- S. aureus had long standing resis. to antibiotic drugs
- *as you increase amount of antibiotic used, prevalence of resis. goes up (exposure)
- increase over time of % of resis. strains of N. gonarrhaea b/c of increased exposure
- yes, there’s sociological factors at play, but in add. to that - geography
Preventing Antibiotic Resistance
- Infection prevention (have ways to stop spread - understanding & education is critical to min. # of infections)
- Rapid and conclusive diagnosis (to quickly identify what a person is infected with so you can chose an antibiotic that at v. least is specific to that infection *step a patient down - don’t know what they’re infected with but clear that need antibiotics b/c infection is life threatening, so you give them an antibiotic that’ll cast a wide net but then when you get conclusive diagnosis you use an antibiotic that’s a bit more narrow/tailored to what you have so you can help to preserve some of their good bact & min. resis. b/c not exposing as many organisms to that drug)
- Appropriate/prudent use of antibiotics (prescribe antibiotic to appease patient if they are demanding, but if its a viral infection, it’ll have 0 utility & patient experiences placebo effect & now allowing bact to dev. resis. that they can pass along to actual organism if ever it does come into body - *1 of the best ways to get resistance)
- Prevention of transmission (cough into elbow, use condum etc.)
