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MedChem 561 > Midterm #1 > Flashcards

Midterm #1 Flashcards

1
Q

Antibiotic Impact on Healthcare

A
  • Make up a substantial amount of prescriptions
  • Places where use is most intense leads to greatest resistance (Ex: ICU)
  • Frequently prescribed unnecessarily
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2
Q

Antimicrobial vs. Antibiotics

A
  • Antimicrobial:
    • Microbial secondary metabolites or synthetic compounds that is small doses inhibit the growth and survival of microorganisms without serious toxicity to the host
  • Antibiotics:
    • Natural subset of antimicrobials
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3
Q

What percent of us is bacterial?

A
  • >90%
  • Targeting pathogenic bacteria with antibacterials will impact our normal flora
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4
Q

Impact of antibiotics on our microbial flora

A
  • Not specific enough to only target the primary pathogen
    • Potentially act against other species of our flora
  • Can compromise the balanced bacterial ecology, especially of the gut
    • e.g. leading to diarrhea (antibiotic associated diarrhea AAD) and C. difficile overgrowth
  • The flora can be reservoirs for transferrable resistance factors (R-factors)
    • R-factors can be detected even during the course of therapy, and persist for years after antibiotic therapy
    • plasmids
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5
Q

Ways commesal bacteria impact our health

A
  • Organs and internal tissues are normally sterile
  • Commensal bacteria do colonize “exterior” including skin, gut, respiratory tract, mouth, eyes, urogenital tract, etc.
  • Provide:
    • Aid in digestion of food and production of vitamins, link to obesity
    • Processing of nutrients and drugs in our guts
    • Overall metabolite profile (metabolome) of host with natural bacterial flora is significantly different from those that are germ-free
    • Prevent establishment of pathogenic competitors
    • Immunity
    • Imbalance can impact asthma
  • Affect can persist and lead to long-term health consequences
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6
Q

Enterotypes

A
  • Microbiome of gut can be categorized into 3 different “enterotypes” each dominated by a main genus
    • Bacteroides
    • Prevotella
    • Ruminococcus
  • Not related to nation, gender, age, or ethnicity
  • May be linked to long-term diet
  • There may be a link between the enterotype found in an individual and susceptibility to disorders/disease
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7
Q

Sources of pathogenic bacterial infections

A
  • organs and internal tissues are normally sterile. Commensal bacteria do colonize “exterior”.
  • Opportunistic pathogens: when commensal bacteria gain acess to interior
  • Compromised immune systems
  • Some pathogens are extrinsic and are not related to our commensal flora
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8
Q

Sinusitus

A
  • S. pneumoniae
  • H. influenza
  • M. catarrhalis
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9
Q

Acute otitis media

A
  • M. catarrhalis; 90-95% produce beta-lactamases
  • S. pneumonia
  • H. influenza
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10
Q

Community acquired pnumonia

A
  • S. pneumoniae
  • H. influenzae
  • S. aureus
  • anaerobes
  • other Gram -
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11
Q

Hospital acquired pnumonia

A
  • Pseudomonas auerginosa
  • Staph. aureus
  • Klebsiella pneumoniae
  • Enterobacteriaceae
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12
Q

Urinary Tract Infections

A
  • E. coli
  • Staphlococcus saprophyticus
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13
Q

Nosocomial UTI

A
  • Klebsiella
  • Proteus
  • Enterobacter
  • Pseudomonas
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14
Q

S. pneumoniae

A
  • Respiratory, sinus and ear infections
  • Streptococcus
  • Gram +
  • Cause of pneumonia
    • 28% resistant to at least one antibiotic
    • 11% resistant to 3 or more antibiotics
    • ​40,000 cases/yr
  • Sinusitis and otitis media (7 M cases/yr)
  • Sepsis (55,000 cases/yr)
  • Meningitis (6,000 cases/yr)
  • Penicillans are front line drug, but not 30% have resistance (PRSP); multi-drug resistance is also seen
  • Vaccine available to help reduce antibiotic resistance
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15
Q

H. influenzae

A
  • Respiratory, sinus and ear infections
  • Gram -
  • aerobe/facultative anaerobe
  • Opportunistic comensal bacteria
  • Pneumonia
  • Sinusitus
  • Otitis media
  • Vaccine (HiB) is available and has reduced frequency of invasive infections relating to encapsulated serotype B
  • 30% beta lactamase producing
  • Some show modified PBPs conferring penicillin resistance, but cepholosporins may be effective, as well as macrolides, fluoroquinolones
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16
Q

M. catarrhalis

A
  • Respiratory, sinus and ear infections
  • Moraxella catarrhalis
  • Gram -, aerobic
  • 75% in children, more prevalent in fall and winter
  • Emerged as a pathogen for children, adults with COPD, immune compromised
  • Otitis media
  • Pneumonia
  • Bronchitis
  • Sinusitus
  • Meningitis, sepsis is rare
  • Lower respiratory tract infections
    • COPD
    • Pneumonia in elderly
    • Hospital outbreaks
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17
Q

Strep. pyogenes

A
  • Gram +, group A beta-hemolytic streptococcus (GAS)
  • Sometimes part of flora, nonpathogenic, asymptomatic
  • Skin and wound infections
    • 10 M cases/yr: cellusitus and impetigo
    • 4500 cases/yr: necrotizing facitis
  • Strep throat
  • Scarlet fever
  • Streptococcal toxic shock: reaction to toxin
  • Acute rhematic fever; autoimmune reaction triggered by strep. pyogenes
  • Penicillin is the drug of choice, very little resistance has emerged; for those penicillin allergic, clindamycin, macrolides
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18
Q

Penicillin, the drug of choice for necrotizing facitis, has little drug resistance. Why then is necrotizing facitis so hard to treat?

A

There is tissue damage that causes poor circulation, so it is hard for the drug to reach the site

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19
Q

Staphylococcus aureus

A
  • Gram +, faculatative anerobe
  • Often found on skin and respiratory tract without causing illness
  • Typical infections:
    • Wound
    • Cellusitis
    • Sinusitus
    • Pneumonia
    • Food poisining
    • Bacteremia (sepsis)
    • Bone (osteomyelitis)
    • Meningitis
    • Endocartitis
    • Toxic shock syndrome (TSS; immune response to protein)
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20
Q

Types of nosocomial infections

A
  • UTI
  • pneumonia and respiratory infections
  • surgery-related
  • skin and mucosa
  • bacteremia
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21
Q

Nosocomial infection: Example: P. aeruginosa

A
  • Gram -, faculatative anerobe/aeobic, opportunist
  • Minimal nutrient requirements
  • Frequent colonizer of medical equipment
  • Burn and wound infections
  • UTI
  • Gastrointestinal
  • Bone and joint
  • Bacteremia (blood infection)
  • Respiratory infections, cystic fibrosis
  • 10% of hospital-acquired infections
  • Significant antimicrobial infections
    • biofilm formation
    • low cellular permeability to antibiotics
    • efflux pumps, multi-drug efflux pumps transports across BOTH membranes
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22
Q

Clostridium difficile

A
  • Gram + anaerobe, spore (infective state) forming
    • while some normally carry the bacteria, most are exposed to it in health care settings; ingested from contaminated surfaces, contact
    • Spores are resistant to antimicrobial therapy, can lead to relapse
  • Gain foothold when gut microbes wiped out or imbalanced
  • Produces enterotoxin (toxin A) and cytotoxin (toxin B) that damage host cells
  • 14,000 deaths/yr in US
  • AAD, fever, abdominal pain
  • Pseudomembranous colitis; a severe infection on the colon
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23
Q

Antibacterials: Drugs

A
  • Sulfa drugs (sulfonamides)
  • Quinolones
  • Linezolid (zyvox)
  • Synthetic products from chemical screens
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24
Q

Bacteriostatic

A
  • ​Some antimicrobials do not necessarily kill the bacteria
  • Break the logarithmic growth phase, allowing the immune system to deal with the infection. Tend to involve inhibition of protein synthesis
  • Ex: tetracyclines, suflonamides, Chloramphenicols, Macrolides, Licosamides
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25
Bacteriacidal:
* Kill the bacterium * Ex: Beta-lactams, Glycopeptides (vanco), Aminoglycosides, Fluorquinolones, Metronizadole * Weaken the cell wall, leading to lysis (ex: penicillins) * Disrupt DNA replications (Quinolones) * Disrupt RNA synthesis (rifampin) * Some drugs that are bacteriostatic at lower concentrations can be -cidal at higher concentrations
26
MIC and MBC
* Minimum inhibitory concentration * Not necessarily kill all the bacteria * Lowest concentration of drug that gives no visible growth after 24h incubation * Minimum bacterialcidal concentration * Concentration of drug that gives no visible growth even in absense of drug
27
Bioavailability
* Before the anti-microbials such as penicillins, arsenicals, and sulfa drugs, topical antiseptics, disinfectants were the only tools available for treating infection * Penicillin in particular provided low host toxicity, high potency that could get to the site of infection and permeate it * The drug must get to its target * Tissue penetration * Penetrate biofilms * Bacterialcidal cell penetration to bind to the target * Attain adequate concentrations to occupy a sufficient number of target active sites to produce desired effect, but without toxicity to host * Must remain bound for sufficient time to inhibit the biological/metabolic process that will lead to bacterial cell death
28
Narrow vs. Broad Spectrum
* Would like narrow spectrum to save normal flora * reduce risk of **antibiotic associated diarrhea** * reduce risk of **C. diff** overgrowth * Often don't know the target or have a superinfection with multiple species * **Empiric therapy **with broad spectrum * Identify pathogen * Switch to narrower spectrum
29
Targets for Antibacterial Drugs
* Ribosomes * Metabolism * Peptidoglycan cell wall * DNA replication machienary * RNA synthesis * **unique to bacteria and not found in humans**
30
Natural Products Antibiotics and their derivatives
* Beta-Lactams * Vancomycin * Cycloserine * Bacitracin * Polymixin * Daptomycin * Rifampin * Rifabutin * Chloramphenicol * Macrolids * Clindamycin * Aminoglycosides * Tetracyclines * Tigecyclines * Quinupristindalfoprisitin * Telithromycin
31
Synthetic Antimicrobial Agents
* Isoniazid * Ethambutol * Quinolones * Metronidazole * Clofazimine * Linezolid * Sulfonamides * Dapsone * Trimethoprim * Para-aminosalicylic-acid
32
MOA: Broad Array of Drug Classes
Diversity of chemical structures
33
Details in Choosing Antibiotic
* ​Differences among bacterial species mean a drug will only be active against certain types of bugs * Narrow vs. Broad spectrum * Gram + vs. Gram - * Target expressed? * Details of target enzyme structure * Differences in resistance mechanisms
34
Gram Positive Bacteria Cell Wall
* Relatively simple cell wall * Single membrane * Thick peptidoglycan layer * High internal osmolality * Less developed biosynthetic capability * Lysozyme, a protein in our innate immune defense, digests peptidoglycan; found in mucus, tears and saliva
35
Gram Negative Bacteria
* complex cell wall * Outer and inner membranes * Thin peptidoglycan, one 1 or 2 layers * Periplasmic space separating the membranes * Porin channels in outer membrane can restrict uptake of drug * Low internal osmololity * Highly developed synthetic capabillty * Highly adaptive
36
Gram Positive Bacteria: Close up of cell wall
* PBP: Penicillin Binding Protein (transpeptidases)
37
Gram Negative Bacteria: Close up of cell wall
* More complex * Outermembrane adding additional protection * Beta-lactamases concentrated in the periplasmic space
38
Porins
* Large, bulky drugs (e.g. vancomycin), \>700 Da exculded * Apolar compounds are excluded * Smaller, polar compounds may cross outer membrane via porins * Drastically limit the uptake of drugs
39
Example of drugs and crossing porins
* PenG is apolar and can't cross through the porins * Ampicillin is made polar with the amino group, can cross through the porin channel
40
Which is harder to treat, Gram + or Gram -?
* Gram - * Because they have an outermembrane they are intrinsically resistant to some drugs
41
How cell wall synthesis inhibitors work?
* Target peptidoglycan cell wall * It's biosynthesis and maintenance * Generally bacterialcidal
42
Stages of biosynthesis in which drugs can affect cell walls
* ​Intracellular * Transport * Extracellular
43
How protein syntheis inhibitors work?
* target the bacterial ribosomes * Shut down protein translation and elongation * Generally bacteriostatic
44
Drugs that attack bacterial ribosome
* Tetracyclines * Macrolides * Aminoglycosides * Chloramphenicol * Lincosamides
45
How drugs attack the ribosome
* 70s (30+50) ribosome is very different than eukaryotic 80s (40+60) ribosome * Antibacterials can bind to many different targets in the ribsome * 30s * tetracyclines * Aminoglycosides * 50s * chloramphenical * macrolides * lincosamides * streptogramins * linezolid
46
How Macrolides Work
* Bind 50s * Induce premature dissociation of peptidyl-tRNA from ribsome, hence premature termination * Prevent addition of residues onto nacsent polypeptide by blocking A to P translocation
47
How Tetracyclines works
* Bind to 30s * Prevent aminoacyl-tRNA binding, hence peptide elongation
48
How Aminoglycosides Work
* Bind to 30s subunit * Prevent tRNA movement from A to P site * Induce errors into "proofreading" and induce premature release of nonsense peptides
49
How Quinolones/Fluroquinolones work
* Helicases during DNA replication induce supercoiling and **gyrase** (a topoisomerase) uncoils * Block topo II and IV (-, +) inhibits gene reguatlion * The nuclease domain still functions properly * DNA gets fragmented and ends up killing the bacterium * Pass through porins * Bacterialcidal * Ciprofloxicin, levofloxicin
50
How rifamycins works
* From Actinobacteria *Amycolaptis mediteranie* * Binds to bacterial RNA polymerase, inhibit RNA synthesis by blocking chain elongation, blocks mRNA transcription * Bacterialcidal * Treatment of mycobacterial infection, some grm + * Some activity against HIVs reverse transcriptase (not clinically tested)
51
Folic Acid Synthesis Inhibitors
* Inhibiton of folate synthesis in bacteria * Sulfa drugs (sulfonamides); an "**antimetabolite**" that inhibits dihydropteroate synthase by competitive binding with p-aminobenzoic acid (PABA) * Folate is crucial for DNA synthesis * Bacteria make their own folate, we do not synthesize our own * Prontosil, the original sulfonamide drug (actually a prodrug) * Trimethoprim/Sulfamethoxazole (TMP-SMX) synergistic
52
The nightmare of CRE
* Carbapenem-resistance enterobacteriacea * Resistant to all or nearly all drugs * High mortality rates * Spread their resistance to other bacteria
53
Resistance: Definition?
* The continued growth of microorganisms in the precense of cytotoxic concentrations of antimicrobial therapeutics
54
Mutant Selections Window
Apply antimicrobial and the strong survive
55
Vertical Transfer of Antibiotic Resistance
* Mutation that allow bacteria to be resistance, then it transfers that to its prodigy
56
MPC
* ​Mutant Prevention Concentration * The inhibitory concentration (MIC) for the most resistant mutant in the population * If [drug]\>MPC, resistance does not emerge * If MIC\<[drug]
  • Serum drug concentration should remain above MPC
  • Combination therapies?
    •
    57
    Acquisition of Resistance: Mutation + Vertical Transfer
    * Spontaneous mutation * Single mutation rarely leads to complete resistance * Infection contain \>1010 cells, infection in 1 of 106-8 * Selective pressure leads to selection of mutant with more resistance to drug, * descendants will posses resistance too (**vertical transfer**) * Example: MRSA
    58
    Acquisition of Resistance: Horizontal Transfer
    * Transformation: * Uptake of genetic material from a cell's surroundings; e.g resistance-encoding DNA from a lysed neighboor; often involves the same species * Transduction: * Bacteriophage transfer genetic pieces from one bacterium to another * Important in *Staph. aureus* * Bacteriophages infect specific species, more likely to get transfered between like species * Conjugation: * A plasmid may be transferred from one bacterium to another * Can be between different species, even between gram+/-
    59
    Conjugation: plasmids
    * Multi-drug resistance can be encoded on a single plasmid * Can be between bacteria of different genera * Transposons: gene with insertion sequences at both ends, which can jump from plasmid to chromosome to plasmid * Gut bacteria serve as reservoirs for plasmids encoding resistance genes
    60
    Resistance and Fitness
    * Costly to maintain plasmids when antibiotic not present; less-fit will be outcompeted by more fit when antibiotic withdrawn; resistance fades * Can take advantage of this by cycling antimicrobials to control resistance * BUT: * Comepentasory mutations can restore fitness * Some resistance mutation don't have a cost * Resistance mutation may improve fitness even in abcense of antimicrobial * These can causes resistance to persist indefinently (even with antibio is removed)
    61
    Molecular Mechanisms of Antimicrobial Resistance
    * **Destroy the drug** * Beta-lactmases * Aminoglycoside kinases * **Modify the drugs target** * PBP modified to prevent methicillin binding in MRSA * PBP mutated in penicillin resistant strep pneumo * **Efflux pumps** * **Modify porin selectivity** * Aminoglycoside resistance in Pseudomonas * **Thicken the cell wall** * VISA * **Other ways to counter drug's action on their targets: Rescue proteins** * R-factor encoded proteins (QNR gene) can bind the DNA gyrase and protect it from a fluroquinolones action * Proteins bind to ribosomes and rescue function in prescence of drug (tetracyclin)
    62
    Beta-Lactam Drug Structure/Function
    * Ring in penicillin and cephlasporins * Beta-lactamases hydrolyze the beta-lactam ring * Enzymatic turn-over of drug inactivation * Beta-lactam normally binds transpeptidase and prevents it from crosslinking the cell wall * beta-lactamases fuck up the beta lactam so it can't bind to the transpeptidase
    63
    Gram + bacteria beta lactamases
    * Primarily in *staphlococci* * SA makes a narrow activity penicillinase * Many gram + do not make beta lactamases * Usually plamid mediated * Constitutive "always on" expression generally * Excreted to surrounding environment, thus lowers extracellular antibiotic concentration
    64
    Gram - bacteria beta lactamases
    * Constitutive or inducible beta lactamases * Concentrated in periplasmic space, lowers intra but not extracellular levels of drug * Plasmid encoded beta-lactamases (constitutive) * Hflu, gonohorrea, salmonella, shigella, e coli, klebsiella * Inhibited by beta-lactamase inhibitor like clauvuanic acid * Chromosomollay encouded beta-lactamases (inducible) * Enterobacter, Citrobacter, Psuedomonas, Serratia, Morganelli, Providencia * Noto inhibited by beta-lactamse inhibitors * Hundred of known beta-lactamase enzymes with different beta-lactam targets * Some have broad specifity

    MedChem 561 (1 decks)

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