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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
Q

Bacteriacidal:

A
  • 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
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26
Q

MIC and MBC

A
  • 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
Q

Bioavailability

A
  • 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
Q

Narrow vs. Broad Spectrum

A
  • 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
Q

Targets for Antibacterial Drugs

A
  • Ribosomes
  • Metabolism
  • Peptidoglycan cell wall
  • DNA replication machienary
  • RNA synthesis
  • unique to bacteria and not found in humans
30
Q

Natural Products Antibiotics and their derivatives

A
  • Beta-Lactams
  • Vancomycin
  • Cycloserine
  • Bacitracin
  • Polymixin
  • Daptomycin
  • Rifampin
  • Rifabutin
  • Chloramphenicol
  • Macrolids
  • Clindamycin
  • Aminoglycosides
  • Tetracyclines
  • Tigecyclines
  • Quinupristindalfoprisitin
  • Telithromycin
31
Q

Synthetic Antimicrobial Agents

A
  • Isoniazid
  • Ethambutol
  • Quinolones
  • Metronidazole
  • Clofazimine
  • Linezolid
  • Sulfonamides
  • Dapsone
  • Trimethoprim
  • Para-aminosalicylic-acid
32
Q

MOA: Broad Array of Drug Classes

A

Diversity of chemical structures

33
Q

Details in Choosing Antibiotic

A
  • ​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
Q

Gram Positive Bacteria Cell Wall

A
  • 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
Q

Gram Negative Bacteria

A
  • 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
Q

Gram Positive Bacteria: Close up of cell wall

A
  • PBP: Penicillin Binding Protein (transpeptidases)
37
Q

Gram Negative Bacteria: Close up of cell wall

A
  • More complex
  • Outermembrane adding additional protection
  • Beta-lactamases concentrated in the periplasmic space
38
Q

Porins

A
  • 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
Q

Example of drugs and crossing porins

A
  • 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
Q

Which is harder to treat, Gram + or Gram -?

A
  • Gram -
  • Because they have an outermembrane they are intrinsically resistant to some drugs
41
Q

How cell wall synthesis inhibitors work?

A
  • Target peptidoglycan cell wall
    • It’s biosynthesis and maintenance
  • Generally bacterialcidal
42
Q

Stages of biosynthesis in which drugs can affect cell walls

A
  • ​Intracellular
  • Transport
  • Extracellular
43
Q

How protein syntheis inhibitors work?

A
  • target the bacterial ribosomes
    • Shut down protein translation and elongation
  • Generally bacteriostatic
44
Q

Drugs that attack bacterial ribosome

A
  • Tetracyclines
  • Macrolides
  • Aminoglycosides
  • Chloramphenicol
  • Lincosamides
45
Q

How drugs attack the ribosome

A
  • 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
Q

How Macrolides Work

A
  • 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
Q

How Tetracyclines works

A
  • Bind to 30s
  • Prevent aminoacyl-tRNA binding, hence peptide elongation
48
Q

How Aminoglycosides Work

A
  • Bind to 30s subunit
  • Prevent tRNA movement from A to P site
  • Induce errors into “proofreading” and induce premature release of nonsense peptides
49
Q

How Quinolones/Fluroquinolones work

A
  • 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
Q

How rifamycins works

A
  • 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
Q

Folic Acid Synthesis Inhibitors

A
  • 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
Q

The nightmare of CRE

A
  • Carbapenem-resistance enterobacteriacea
  • Resistant to all or nearly all drugs
  • High mortality rates
  • Spread their resistance to other bacteria
53
Q

Resistance: Definition?

A
  • The continued growth of microorganisms in the precense of cytotoxic concentrations of antimicrobial therapeutics
54
Q

Mutant Selections Window

A

Apply antimicrobial and the strong survive

55
Q

Vertical Transfer of Antibiotic Resistance

A
  • Mutation that allow bacteria to be resistance, then it transfers that to its prodigy
56
Q

MPC

A
  • ​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]<mpc>
    </mpc><li>Serum drug concentration should remain above MPC</li><li>Combination therapies?</li>

</mpc>

57
Q

Acquisition of Resistance: Mutation + Vertical Transfer

A
  • 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
Q

Acquisition of Resistance: Horizontal Transfer

A
  • 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
Q

Conjugation: plasmids

A
  • 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
Q

Resistance and Fitness

A
  • 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
Q

Molecular Mechanisms of Antimicrobial Resistance

A
  • 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
Q

Beta-Lactam Drug Structure/Function

A
  • 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
Q

Gram + bacteria beta lactamases

A
  • 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
Q

Gram - bacteria beta lactamases

A
  • 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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