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antibiotics and antibiotic resistance Flashcards

1
Q

what are antibiotics and selective toxicity

A

antibiotics are molecules that kill bacteria or inhibit their growth (can be natural or synthetic)

Clinically useful antibiotics: inhibit the cellular processes in bacterial cells and elicit a toxic effect of the bacteria but not the human (SELECTIVE TOXICITY)

Selective toxicity: antibiotics target gene products found on bacterial cells, not human cells (IE petidoglycans)

allows minimal side effects

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2
Q

disinfectents vs antiseptic vs antibiotics

A

disinfectants: toxic to humans and bacteria (think bleach) used to clean inanimate objects

Antiseptics: (generally toxic to bacteria, nonspecifc effects, too toxic for humans ingestion-alcohol) good for topical use

Antibiotics: target specific cellular processes, exhibit effects on bacteria but not on humans only thiing that has selective toxicity can be used systemically

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3
Q

bacteriostatic vs bacteriocidal

A

not completely absolute- but represent the major effect

bacteriostatic-inhibit growth but dont kill, immune system will eradiccate

bactericidal- kill bacteria directly (important for HIV, device infections, and endocarditis)

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4
Q

pharmacology/ bioavailability

spectrum of activity

A

pharmacology/bioavailability: not all antibiotics penetrate all tissues equally, to be effective antibiotics need to get to site of infection

spectrum of activity: what different species are susceptible to a given antibiotc

narrow spectrum: effective against a relatively small group of bacteria (only aerobic gram positive bacteria)

broad spectrum: effective against a wide range of bacteria (gram positive and gram negative bacteria)

advantage: can be used when infectious agent is unknown or in emergency
disadvantage: affects many members of natural microbiota leading to secondary effects (diarrhea, antibiotic resistance)

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5
Q

measuring antibiotic susceptibility of bacteria

A

susceptibility- bacteria are susceptible to an antibiotic if they stop growing in antibiotic concentrations in a patient
its measured in lab with pure cultures

bacteria NEED TO BE SUSCEPTIBLE to antibiotics to be clinically effective

not all bacterial species are susceptible to the same antibiotic, so you need to know the bacteria causing infection and the antibiotic susceptibility profile for that specific isolate (antibiogram)

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6
Q

Measuring antibiotic susceptibility of bacteria

A

bacterial growth in liquid medium: quantitative approaches

MIC (minimum inhibitory concentration) defines the lowest concentration of antibiotic that inhibits growth

Minimum bactericidal concentration (MBC) defines lowest concentration of antbiotic that kills a defined proportion of bacterial population after specified time

Disk diffusion test: inoculate agar plate, add Abx disk, measure zone of inhibition (Qualitative)

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7
Q

unintended consequences

A

toxic side affects of drugs: tetracycline (discoloration of teeth), streptomycin (auditory damage), chloramphenicol (anemia)

hypersensitivity: anaphalaxys in responce to penicillin

alteration of normal gut microflora (antibiotic-associated diarrhea/enterocolitis- clostridium dificil) C. diff. will flourish under antibiotics bc the floura dies and the c.diff grows, causing release of endotoxins A and B- diarrhea

selection for antibiotic resistance

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8
Q

how do bacteria become antibiotic resistant

A

thru genotypic changes that enable growth in the presence of an antibiotic:

horizontal gene transfer: foreign DNA encoding resistant genes -rapid milti drug resistance (resistant DNA is transferred between bacteria)

Spontaneous mutation: selection for growth in large populations of bacteria (random mutation is selected for bc of its resistance)

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9
Q

how do bacteria overcome inhibition by antibiotics

A

3 basic mechanisms: mixed and matched:

  1. Modification (inactivation) of antibiotic molecule itself (cleavage of beta-lactams by beta-lactamases, enzymatic modification of aminoglycosides, chloraamohenicol (cat) (beta lactamase)
  2. Modification (reprograming) of antibiotic target
    (point mutations in gyrA, rpoB, ribosomes, PBPs, alt. peptidogylcan structure for vancomycin resistance)

3.Reduction of antibiotic concentration/prevent access to the target
efflux pumps (spit out the antibiotic can be broad or specific)
altered cell envelope to enhance permiability (thru porins modifications)

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10
Q

how do antibiotics inhibit bacterial growth?

A

The main cellular processes:
1. Peptidoglycan synthesis: target of antibiotics (B-lactams, Vanocomycin, Bacitracin, Fosfomycin, D-cycloserine)

  1. RNAP and RNA synthesis: Rifampin, Fidaxomicin
  2. Key Metabolic reactions: Trimethoprim, Sulfamethaoxazole
  3. Cell membrane: (Polymyxins, Daptomycin)
  4. DNA Replication and Repair: (Fluoroquinolones and Metronidazol)
  5. Ribosomes and Protein Synthesis (Tetracyclines, Aminoglycosides, Macrolides, Oxazolidinones, Clindamycin, Chloramphenicol, Tigecycline)
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11
Q

Peptidoglycan biosynthesis

A

Stage 1: synthesis of MurNAc pentapeptide precursors-cytoplasm (ends with D-ala-D-ala)

Stage 2: lipid linkage and transport of disaccharide precursors across membrane

Stage 3: polymerization and crosslinking of precursors into peptidoglycan- extra cellular (VIA PBPs aka penecillin binding proteins)

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12
Q

peptidoglycan as a target for antimicrobials concept

A
  1. peptidoglycan must be synthesized during growth for it to work
  2. provides structural support for bacteria not to get lysed due to osmotic pressure
  3. peptidoglycan and enzymes used to synthesize it are unique to bacteria so good target
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13
Q

Beta-lactam antibiotics

A

act by blocking peptidoglycan crosslinking by preventing the enzyme PBPs (thru mimicing the PBP structure)

4 basic types- all work the same way by inhibiting PBP from cross-linking peptidoglycans

  1. Penecillin (all end in -cillin) peni-, amp-, amox-, methi-, oxa-, ticar-, pipera-
  2. Carbapenem (all end in -penem) imi-, mero-, erta-, dori-,
  3. Cephalosporin (all start with ce-) -fazolin, -phalexin, -furoxime, foxitin, ftriaxone, ftazidime, fepime
  4. Monobactam aztreonam
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14
Q

Primary mechanism of resistance to B-lactam antibiotics

A

production of an enzyme called b-lactamase catalyzes the enzymatic inactivation of B-lactam antibiotics (cleavage of B-lactam ring) *B-lactamase cuts B-lactam preventing it from working

  • some bacteria have B-lactamase encoded in their genome
  • often encoded on plasmids that are easily transfered to other bacteria
  • recently ESBLs (extended spectrum B-lactamases) have broad spectrum to inactivate many different types of B-lactams (primarily in gram negative bacteria
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15
Q

Other mechanisms of resistance to B-lactams

A
  1. reduced permeability- some B-lactams have a reduced permeability intrinsically (usually gram- bacteria have mutatations in the porins) reducing access to PBPs
  2. Altered PBPs- prevent binding of B-lactams (common in penecillin resistant Streptococcus and methicillin resistant Staphylococcus aureas MRSA
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16
Q

inhibiting B-lactamase thru B-lactamase inhibitors

A

Clavulanic acid, Sulbactam, tazobactam (share structural features of B-lactam)

inhibitors are not good antibacterials

they bind to B-lactamase and are released very slowly (to form inactive complex) to inhibit B-lactamase (only works on a few B-lactamase

inhibitors are given w/ B-lactams

17
Q

Peptidoglycan inhibitor: Glycopeptides aka vancomycin

A

they also inhibit PBPs

Glycopeptides are glycosylated, non-ribosomal synthesized PEPTIDE antibiotics

Mechanism of action: Vancomycin binds to D-ala-D-ala at the end of a peptide side chain in a peptidoglycan precursor, blocking PBPs from working to transglycosylate/transpeptidate

effective on gram+ only (bc gram- have outer membrane…permeability)

Often used for B-lactam resistant infections MRSA or in patients with B-lactam hypersensitivity

18
Q

Vancomycin resistance

A

Bacteria modify the target- they use genes that dont use D-ala-D-ala but use D-ala-D-lac so that vancomycin cant bind

these genes are also on plasmids that are easy to transfer

Vancomycin resistance is associated with enterococci in hospital settings (VRE- vancomycin resistant enterococci)

19
Q

Cycloserine (peptidoglycan inhibitor)

A

similar to D-alanine (used as an anti-TB therapy)

competitive inhibitor of D-ala in two reactions with Alanine racemase and D-Alanyl-D-alanine synthetase

20
Q

Bacitracin

A

peptide antibiotic- too toxic for systemic use

Mechanism of action- binds to pyrophosphate on the lipid carrier for peptidoglycan precursors and blocks recycling

prevents peptidoglycan synthesis

Group A strep are sensative,

21
Q

Agents that attack cell envelope

A
  1. Daptomycin- lipopeptide (lipid modified peptide) bacteriocidal narrow spectrum (gram+) it binds to and disrupts cytoplasmic membrane
  2. Polymyxins (polymyzin B, colistin)- lipopeptide antibiotics- bactericidal narrow spectrum (gram-) toxic

binds to LPS so it disrupts the outer and inner membrane

both help with antibiotic resistance

22
Q

antimicrobials that inhibit protein synthesis (translation)

A

bacterial ribosomes are 30 and 50s but humans are 40 and 60 s

protein synthesis occurs in 2 phases initiation (formed by 30 s subunit) and elongation (when 50 s comes along)

23
Q

Protein syntesis inhibitors targeting the 30 s function

A

Tetracyclines (tetracycline, doxycyckine, minocycline)

BACTERIOSTATIC, broad spectrum

Mechanism of action: binds to 30S ribosomal subunit and interferes with the binding of aminoacyl tRNA to the ribosomal complex- problems of creating the 70s

different drugs target different R positions

Tigecycline- new drug that is the same as tetracyclines but binds to other locations on 30s as well avoids resistance

24
Q

Resistance to tetra cycline

A
  1. tetracycline efflux pump (reduction in concentration) most common and causes a resistance to all tetracycline family Abx
  2. mutations on the ribosome (modifies the Abx target)
25
Q

Aminoglycosides

A

protein synthesis inhibitors that target the 30s function
BACTERICIDAL (only bactericidal ribosomal inhibitor)

Mechanism: binds irreversibly to 30s, stops initiation, causes premature release of MRNA from ribosome, causes misreading (fucked up AA sequence->fucked up protein)

good for hard to kill gram- (pseudomonas aeruginosa)
doesnt penetrate gram+, and anaerobes
adverse effects: cytotoxic
Mechanism of resistance: enzymatic modification of the Abx to prevent aminoglycoside binding to the ribosome

26
Q

Macrolides

A

erythromycin, azithromycin, clarithromycin

Bacteriostatic, used primarily against gram+
useful with allergies to b-lactams
does not cross outer membrane of gram-

Mechanism: binds to 50s blocking elongation

Resistance: 2 ways
1. enzymatic modification (methylation) of Ribosomal RNA (erm gene causes erythromycin to not bind to methylated ribosome) mod of target- usually plasmid born

  1. efflux pumps- pumps out the Abx
27
Q

Clindamycin

A

Bacteriostatic
inactive for gram- aerobes
useful for community acquired MRSA but not hospital MRSA
often used to treat infections by toxin-producing S. aurereus (toxins are proteins) but responsible for C.diff colitis

Mechanism of action: binds 50s ribosomal subunit to block elongation

Resistance:
enzymatic mod (methylation via erm gene of rRNA) clindamycin cant bind

exhibits cross resistance with macrolides

28
Q

chloramphenicol

A

bacteriostatic, broad spectrum

Potential toxicity , used rare (for typhoid, rockymountain)

it inhibits ribosomes in mito (toxic to all cells)

Mechanism of action: binds 50s ribosome subunit to inhibit elongation

Mechanism of resistance: bacterial enzyme (CAT) catalyzes ADDITION OF ACETYL GROUP TO THE DRUG preventing ribosome binding by the drug (modification of antibiotic) typically plasmid borne

29
Q

Linezolid

A

oxazolidnone fam

Narrow spectrum- not effective against gram- or anaerobes

oral availability
Mechanism of action: binds to a special spot on 50s to precent 70 s

lots of resistance

Mechanism of Abx resistance:
point mutations in ribosomal rRNA that prevent linezolid binding (modification of Abx target) - no cross resistance with other ribosome-targeting Abx

30
Q

Quinolones

A

inhibitor of DNA replication

Original: Nalidixic acid
Mechanism of action: Binds to bacterial DNA gyrase and topoisomerase to inhibit catalytic function- disrupts DNA replication and repair
Problems: narrow anti microbial spectrum/rapid selection for resistant mutants

Clinically useful: fluoroquinolones (norfloxacin, ciprofloxacin, moxifloxacin, levofloxacin)
all quinolones exhibit the same mechanism

Mechanism of resistance: 2 ways

  1. point mutations in bacterial DNA gyrase prevent antibiotic binding and enzyme resistant to the action of quinolones (modify the target)
  2. efflux pump-mediated and altered porin resistance also observed
31
Q

Metronidazole

A

used to treat anaerobic bacterial infections (used for C. diff)
mechanism of action: in an anaerobic environment, bacteria produce radicals, a toxic metabolite that damages the DNA (essentially bacteria take up metro and activate it which causes metro to be toxic to bacteria)

Bactericidal

Mechanism of resistance: alterations in metaboloic pathways cause bacteria to lose ability to reduce the nitro group

32
Q

Rifamin (rifampicin) and Fidamicin

A

both bactericidal

Rifampin:
Mechanism: Binds to B subuit of bacterial RNAP to inhibit RNA synthesis
Problem: rapid resistant mutants
Mechanism of resistance: mutations of B RNAP

Fidaxomicin:
Mechanism of action: noncompetitive inhibitor of RNA synthesis by binding to RNAP

Mechanism of Resistance: same as Rifampin

33
Q

Anti-folates

A

Metabolic analogs that act as Abx
Metabolic analogs-structurally similar to metabolic intermediates- and the analogs act as comp. inhibitors to block normal pathway

Tetrahydrofolate biosythnesis path is targeted in bacteria

Sulfonamides (sulfamethoxazole, sulfadiazine)
Trimethoprim

Mechanism of resistance (gene encoding a dihydrofolate reductase or mutations in the gene encoding typically plasmid born

34
Q

Bacterial Growth

A

Most pathogens are mesophilic (grow at temps of 20- 40 C) Campylobacter is thermophillic and grows at 42 C

Pathogenic bacteria grow at a pH of 7.2-7.6

growth phases: lag, exponential, stationary, death

35
Q

Antibiotic Side effects

A 
All antibiotics-> Antibiotic diarrhea (C. Dificile)
Tetracycline-> discoloration of teeth
Aminoglycosides-> Auditory damage
Chloramphenicol -> Aplastic anemia
Penicillin-> Anaphylactic shock

bacteriology (19 decks)

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