B: Human Control

Question 1

mechanism of action

Answer 1

drugs affecting bacterial growth

Question 2

considerations and types:
selectivity
-premise?
-feasibility?
target effects?

Answer 2

-Premise: Target pathogen while minimizing host damage
-Feasibility: Bacteria ↑↑, Eukaryotes ↓
-Target effect:
– Cell wall
– Protein synthesis
– Cell membrane
– Metabolism
– Nucleic Acid syntheses
– Attachment and Recognition

Question 3

methods:
cell walls

Answer 3

-Osmotic protective barrier

-Drugs: Inhibit new wall production → Osmotic rupture

-Bacterial:
–PG = NAM + NAG: Protein cross-link
–Reps:
-β-lactams: Anti-enzymatic (Synthesis)
» Penicillin→ Methicillin→ cephalothin
-Monobactams: Against G- aerobes
-Anti-crosslinkers (wall): Vancomycin →Cycloserine
-Anti-transport: Bacitracin
-Anti-waxy layer: Isoniazid [INH], Ethambutol

-Fungal:
–Echinocandins: Against glucan crossslink

Question 4

protein synthesis: recall central dogma

Answer 4

-Recall: Central Dogma
–Protein Synthesis: Ribosomes
* 2 Subunits
– Both: tRNA docking and Initiation
– Small: Codon reading
– Large: Peptide bond formation

• Comparison
  – Prokaryotes: 30S + 50S = 70S
  – Eukaryotes: 40S + 60S = 80S
• Pros & Cons
  – Genetic differences
  – Genetic similarities (Mitochondria)

Question 5

protein synthesis: 30S targeting

Answer 5

-Aminoglycosides: 3D morphology
-Reps:
– Streptomycin, Gentamycin

–Tetracyclines: Block tRNA docking (A-site)
-Reps:
– Doxycyclin

Question 6

protein synthesis: 50S targeting

Answer 6

50S targeting: Progress Interference like Bacteriostatic
–Chloramphenicol [CAM]: Inhibit substrate binding
–Lincosamides, Streptogramins, Macrolides: Block sterically progression
-Reps: Erythromycin which is Preferred for PEN-
resistance

–Oxazolidinones: Block initiation of TLN, Limited usage (IV) (Rep: Cycloserine)

Question 7

antisense technology

Answer 7

ssNucleic Acids
– Complementary to pathogen
NA’s
– Block initiation of TLN

Question 8

membranes

Answer 8

Membrane disruption:
– Channel and Pore formation
– Target lipids from cell membranes

Gramicidins:
– Pentadecapeptides
– Target G+ (except bacilli) and some G-
– Topical: Hemolytic
– Reps: Gramicidin A, B, C (=D), S (Neosporin)

Polymyxins:
– Synthesized by B. polymyxa spp.
– Target G- (Pseudomonas spp)
– Limited use

Others:
– Pyrazinamide: M. tuberculosis
– Anti-helminthics: Praziquantel, Ivermectin

Question 9

membranes:

Answer 9

Polyenes
– Synthesized by Streptomyces spp.
– Conjugated carbon chains: UV absorptive (yellow)
– Fungicidal (antimycotic): Target Ergosterol (~cholesterol), C.T. Most bacteria do not produce sterols
– Reps: Nystatin, Amphotericin B

• Azoles/Allylamines
  – Anti-enzymatic: Target Ergosterol synthesis
  – Reps: Fluconazole, Myconazole

Question 10

metabolism

Answer 10

Common poor targets
– Glycolysis
– Fermentation

• Anti-metabolic agents
• Sulfanilamides
  – Bactericidal
  – Analogs of PABA: Co-factors for NA’s synthesis, No effect on humans (Folic Acid)
  – Reps: Sulfamethoxazole, Trimethoprim
• Others
  – Atovaquone: Anti-ETC (Fungi/Protozoa)

Question 11

anti-virals

Answer 11

-Targeting viral life-cycle:
– Uncoating: Triggered by acidity of hosts (Lysosomes)
-Reps: Amantadine, Rimantadine
» i.e. Influenza A

– Protease inhibitors:
* Protein-digestive enzymes = Proteases
* Anti-enzymatic: Targets HIV, HxV
* Reps: Ritonavir, Telaprevir

Question 12

NA synthesis

Answer 12

-Judicious use of Analogs
-Typically anti-viral: Polymerases: Eukaryotic have repair mechanisms, Viral, too fast and too often

-Target-based:
–Anti-bacterial: Quinolones, Fluoroquinolones (Anti-replicative (Gyrase))
-Rifampins: Anti-transcriptive (Mycobaterium spp.)
-Clofazimine: Anti-replicative (Mycobaterium spp.)
–Anti-protist: Life-cycle inhibitors, (Pentamidines, Propamidines)
–Anti-viral: Anti-replicative, Reverse-transcriptase inhibitors, HIV, retroviruses
-Attachment antagonists: Novel methods: Arildone

Question 13

evaluation of efficacy

Answer 13

Controlled:
–Phenol Coefficient: Comparison to Phenol over
time, Rideal-Walker C, USDA C
–Use-Dilution: P. aeruginosa, S. enterica, S. aureus metal rods
–Kelsey-Sykes Capacity: Incubation time-removal, Reveals minimal time required for incubation
-Practical: In-Use: Before and After comparison, Real scenarios

Question 14

delivery methods:

Answer 14

PO:
–Simple: Slow
–Auto-administration: Compliance
–Blood Efficacy: Low, Pulsing

IM:
–Hypodermic needles: Pain susceptibility
–Blood Efficacy: Intermediate, Pulsing

IV:
–Hypodermic needle system: Extended permanence
–Blood Efficacy: High, Continuous

Question 15

side effects:

Answer 15

Toxicity: Selectivity of higher effect against
pathogen versus patient, Observable effect in patient
*Circulatory:
– Lungs
– Liver
– Kidneys

• External
  – Skin
  – Mucosa
• Gastrointestinal
  – Oral
  – Stomach
  – Intestines
• Sexual
  – Sterility
  – Libido + Performance

Question 16

side effects:
-allergies
-anaphylaxis

Answer 16

Allergies:
– Type I-Hypersensitivity of immune system (rapid)
–Excessive activation of WBCs (mast cells and basophils) by IgE, resulting in an extreme
inflammatory response: Eczema, hives, rash

Anaphylaxis:
– Systemic vasodilation → Low BP
– Bronchoconstriction

Question 17

safety:

Answer 17

-Superinfections: Normal Microbiota disruption
by broadly-targeting antibiotics: i.e. vaginitis, thrush, colitis
– Commonly affecting immunocompromised
patients

Question 18

considerations

Answer 18

delivery
safety
disruption

Question 19

drug resistance:

Answer 19

is futile

Everyone is “special”:
– Not all organisms are equally sensitive: Intra-population
–via evolution by natural or artificial selection

You can be special too:
–Acquired via, Genomic mutation, Horizontal transfer of R-factors (Transformation, transduction, conjugation)

Question 20

mechanisms

Answer 20

Alteration of drug pathway:
–Cell Wall → Membrane → Intracellular → Molecular Target

Types:
– Inactivation or destruction of drug: Modification of drug
–Prevention or retardation of drug entry
–Metabolic adaptation
–Selection: Resistance pumps
–Target modification

Question 21

MDR:

Answer 21

Multiple Drug Resistance:
–Usually acquired by R-plasmid
–Often created in hospitals: High treatment levels: Eliminates sensitive cells, Supports growth of resistant cells
–Resistant to 3+ drugs
–Cross-resistance: Drug resistance based on
similarities.

Question 22

overcoming resistance:
compliance
cocktails

Answer 22

Compliance: Proper delivery, Maintenance of high concentration, Proper time frame, Limitation of distribution (Avoid indiscriminate use)

Cocktails: Use of multiple antimicrobials to inhibit growth without exception, Drug synergy opportunities

Question 23

MDR-TB

Answer 23

-Multi-drug-resistant tuberculosis
–M. tuberculosis that is resistant at least to isoniazid (INH) and rifampin (RMP