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Microbiology 1 > Lecture #11 - Antimicrobial Drugs & Drug Resistance > Flashcards

Lecture #11 - Antimicrobial Drugs & Drug Resistance Flashcards

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1
Q

Antimicrobial Drugs are used…

A

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)

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2
Q

Antimicrobial Drugs

These are compounds that…

A

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

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3
Q

Antimicrobial Drugs

Two broad categories

A

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)

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4
Q

Antimicrobial Drugs

Can also be described based on whether they are:

A

• 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)

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5
Q

Antibiotic targets include:

Cell wall synthesis

A

can target cell wall with diff categories of antibiotics & it’ll be impacted

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6
Q

Antibiotic targets include:

Targets for nucleic acid syn.

A

capacity to interfere with DNA replication or prod. of RNA transcripts (intermediates b/t DNA & protein)

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7
Q

Antibiotic targets include:

Protein syn.

A

can interfere with ribosomes –> protein syn.

- prevent bact from syn proteins needed for cell function

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8
Q

Antibiotic targets include:

Lipid biosyn.

A

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)

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9
Q

Antibiotic targets include:

Cytoplasmic membrane structure & function

A

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

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10
Q

Antibiotic targets include:

Folic acid metabolism

A

can inhibit pathways for metabolic syn

–> turn down folic acid syn

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11
Q

Cell Wall Active Antimicrobial Drugs

A 
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)
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12
Q

Cell Wall Active Antimicrobial Drugs

Largest class are…

A

beta lactam antibiotics

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13
Q

Cell Wall Active Antimicrobial Drugs

Largest class are beta lactam antibiotics

A

• 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
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14
Q

Cell Wall Active Antimicrobial Drugs

Penicillins

A

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)

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15
Q

Explain how Penicillins target transpeptidation in gram +’s

A

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

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16
Q

Explain Ampicillin (ex of penicilin)

A

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)

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17
Q

Not all penicillins will be…

A

susceptible to B-lactamase enzymes

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18
Q

Cell Wall Active Antimicrobial Drugs

Cephalosporins

A

• 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
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19
Q

Compare & constrast Penicillins & Cephalosporins briefly

A

biochem of drugs are diff (6-mem ring vs 5 mem ring), process it targets is same (both target transpeptidation)

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20
Q

Growth Factor Analogs

A

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)

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21
Q

Growth Factor Analogs

Example: Sulfa drugs

A

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

22
Q

Describe how Sulfa drugs (ex: sulfanilamide) is carried out as well as how it is in combo with another analog (trimethoprim)

A
  • 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

23
Q

Growth Factor Analogs

Example: Isoniazid

A

• 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)

24
Q

Nucleic Acid Synthesis Inhibitors

Quinolones

A
  • 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)

25
Q

Nucleic Acid Synthesis Inhibitors

Quinolones

Example:

A

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

26
Q

Nucleic Acid Synthesis Inhibitors

Quinolones

Example: ciprofloxacin a fluorinated quinolone (fluoroquinolone)

PROBLEM:

A

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)
27
Q

Nucleic Acid Synthesis Inhibitors

Quinolones

Rifampin:

A

binds to RNA polymerase preventing transcription

Outcome: RNA polymerase = inactive

28
Q

Nucleic Acid Synthesis Inhibitors

Quinolones

Actinomycin:

A

Binds to DNA template blocking transcription elongation

  • RNA polymerase can’t get on & assemble nucleotides
29
Q

Protein Synthesis Inhibitors

A

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

30
Q

Protein Synthesis Inhibitors

Include:

A

Aminoglycosides

Tetracycline

Macrolides

31
Q

Protein Synthesis Inhibitors

Include:
• Aminoglycosides

A

• 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

32
Q

Protein Synthesis Inhibitors

Aminoglycosides

Examples include:

A

streptomycin, gentamycin and neomycin

33
Q

Protein Synthesis Inhibitors

Tetracycline:

A
  • 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)
34
Q

For Protein Synthesis Inhibitor - Tetracycline

Why would using an antibiotic on a farm animal be associated with the promotion of growth?

A

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

35
Q

Protein Synthesis Inhibitors

Macrolides

A

• 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

36
Q

Protein Synthesis Inhibitors

Macrolides

Example:

A

erythromycin and azithromycin (naturally occuring)

• Produced by Streptomyces spp.

37
Q

Novel Antibiotics (last ~10 years)

Daptomycin

A
  • 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

38
Q

Methicillin

A

= 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)

39
Q

Novel Antibiotics

Platensimycin

A
  • 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

40
Q

Antibiotic Resistance

A

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

41
Q

Antibiotic Resistance

Resistance is prevalent because of

A

widespread and sometimes incorrect use of antibiotics (can’t let immune system do job if it can, otherwise seek antibiotics)
– Medicine, veterinary medicine, agriculture

42
Q

Antibiotic Resistance Mechanism’s:

A
  • Reduced permeability
  • Inactivation of antibiotic
  • Alteration of target
  • Development of resistant biochemical pathway
  • Efflux
43
Q

Antibiotic Resistance

Mechanism: Reduced permeability

A
  • 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

44
Q

Antibiotic Resistance

Mechanism: Inactivation of antibiotic

A
  • SPECIFIC
  • B lactamase (inactivation by cutting B-lactam ring so no longer effective to interfere with transpeptidase of PD layer)

Ex: Penicillins, chloramphenicol, aminoglycosides

45
Q

Antibiotic Resistance

Mechanism: Alteration of target

A
  • 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

46
Q

Antibiotic Resistance

Mechanism: Development of resistant biochemical pathway

A
  • 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
47
Q

Antibiotic Resistance

Mechanism: Efflux

A

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
48
Q

Which Antibiotic Resistance mechanisms are VERY SPECIFIC TO A CERTAIN ANTIBIOTIC (resis to that 1 but doesn’t provide protection to others)?

A
  • Reduced permeability
  • Inactivation of antibiotic
  • Alternation of target
  • Development of resistant biochemical pathway
49
Q

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)?

A

Efflux

ex: Tetracyclines, chloramphenicol, fluoroquinolones

50
Q

Patterns of Antibiotic Resistance

A

• 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
51
Q

Preventing Antibiotic Resistance

A
  • 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.)

Microbiology 1 (15 decks)

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