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antibacterials 2 a Flashcards

1
Q

how do antibacterials get into bacteria (gram +ve)?

A

a have active peptide transporters
– dipeptide, tripeptide and OligoPePtide transporters (Opp)
– transport most hydrophilic antibacterials directly into the cytoplasm
– hydrophobic antibacterials can use passive diffusion

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2
Q

how do antibacterials get into gram negative bacteria?

A

Gram negative bacteria have Outer Membrane Proteins (porins, Omp) that act as
molecular sieves
– e.g. main porins in E. coli: OmpC and OmpF – allow hydrophilic molecules up to about 600 Da (1.1 – 1.2 nm diameter) to pass into periplasmic space

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3
Q

who targets the cell wall?

A

b-lactams
vancomycin
teicoplanin
isoniazid

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4
Q

what are b-lactam antibiotics?

A

Broad spectrum bactericidal activity against – both G+ve (except aztreonam) and G-ve bacteria

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5
Q

what are the characteristics of b-lactam antibiotics?

A

time dependent action
good distribution:
- increased with greater lipophilicity
-remember polarity
must have low PAE
largely renal excretion

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6
Q

why do we usually not use b-lactams for UTIs?

A

largely renal excreted
– not often used for UTIs to reduce increase in resistance
* treat with other suitable agents, if possible
* can be used for complicated UTIs, if necessary

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7
Q

what is the penicillin SAR?

A
  • Amide and carboxylic acid are involved in binding
  • Carboxylic acid binds as the carboxylate ion (pKa ~ 2.5 – 3.0)
  • Mechanism of action involves the b-lactam ring
  • Activity related to b-lactam ring strain
    (subject to stability factors)
  • Bicyclic system increases b-lactam ring strain
  • Not much variation in structure is possible
  • Variations are limited to the side chain (R)
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8
Q

what are some areas for developements for b-lactams?

A

1* to increase chemical stability for oral administration (stomach acid)
* addition of electron withdrawing groups (R)
* prodrugs (-CO2H)
2* to increase resistance to b-lactamases
* addition of bulky groups (R)
3* to increase the range of activity
* addition of ionisable groups (R)
* addition of ureido groups (R)

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9
Q

what happens to b-lactam structure at physiological ph?

A

All have >99.9% ionised ‘acid’ at physiological pH

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10
Q

what is the MOA of b-lactams?

A

Act upon synthesis of bacterial cell membrane
b-Lactams interfere with peptidoglycan (components of call wall) formation through their interaction with the transpeptidase enzyme [penicillin binding proteins (PBPs)]

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11
Q

what is the consequence of b-lactams inhibiting the formation of cross-links in cell wall?

A

– reduces integrity and strength, eventually leads to cell lysis / death
* high osmotic pressure inside bacterial cells
* when cell wall weakened, easily bursts

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12
Q

what is prokaryotic cell wall composed of?

A

peptidoglycan
– polymer
– sugar units (NAG/NAM)
– cross-linked by peptide uni

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13
Q

what are 3 reasons for potential acid sensitivity?

A
  • (1) Ring strain – acid-catalysed ring opening relieves ring of β-lactam ring
  • (2) Highly reactive β-lactam carbonyl group – resonance stabilisation is not possible for β-lactam ring
  • (3) Influence of the acyl side chain (neighbouring group participation)
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14
Q

what is a solution to acid sensitivity?

A
  • β-lactam ring is vital for antibacterial activity and only the third factor can be
    addressed
    – reduce amount of neighbouring group participation
    – use electron-withdrawing group in side chain to draw electrons away from the
    carbonyl oxygen and reduce its nucleophilicity
    – stability improvements can allow oral administration
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15
Q

what are the 4 mechanisms of resistance to B-lactam agents?

A
  • Most resistance to b-lactam antibiotics due to specific enzymes
    – b-lactamases
    – break open b-lactam ring, which is essential to activity
    – b-lactamase resistance to penicillin first seen in 1940, before clinical use started!
  • Modification of the target protein (PBP)
    – most common in G+ve bacteria, e.g. Haemophilus and Neisseria strains
    – less common in G-ve bacteria
  • Limited uptake into the bacterial cell, especially G-ve bacteria
    – polar molecules, so poor passive diffusion, use porins
    – mutations to porins reduce uptake and confer resistance
  • Increased efflux pump activity
    – up-regulation of efflux pumps causes multi-drug resistance
  • affects many antibiotics (e.g. fluroquinolones, aminoglycosides)
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16
Q

what are the 4 classes b-lactamases are divided into?

A

– active-site serine β-lactamases (SBLs; classes A, C and D)
– zinc-dependent or metallo-β-lactamases (MBLs; class B

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17
Q

how do extended spectrum b-lactamases (ESBLs) work?

A
  • hydrolyse even third generation cephalosporins, but not usually carbapenems
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18
Q

how do carbapenemases work?

A
  • confer resistance to carbapenemases, alongside almost all clinical b-lactam
    antibiotics
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19
Q

how do metallo b-lactamases work?

A
  • broad range of b-lactam substrates, including carbapenems (but not aztreonam)
20
Q

what are b-lactamases in gram +ve bacteria?

A

Beta-lactamases are inducible in G+ve bacteria – produced in response to presence of b-lactam antibiotic

21
Q

what are b-lactamases in gram -ve bacteria?

A

constitutive in G-ve bacteria – they produce the enzyme all the time, whether or not beta-lactam antibiotics are present
– but, only if the G-ve bacterium has the b-lactamase gene
– located in periplasmic space

22
Q

how do b-lactamases work?

A

Generally, have a similar mechanism of action, cleaving the b-lactam ring leading to inactivation of b-lactam antibiotics

23
Q

how are SBLS related to PBPs?

A

– share a similar SER-based amino acid sequence
– Use serine as the nucleophile to hydrolyse β-lactams

24
Q

how do MBLs work?

A

MBLs (class B) have a different hydrolytic mechanism
– use a metal-activated water nucleophile to to hydrolyse β-lactams

25
Q

what are the catalytic important residues of serine b-lactamases in serine?

A

SER64/70

26
Q

what additional mechanism do b-lactamases have?

A
  • Additionally, are hydrolysed to recycle the b-lactamase enzyme
    – not irreversibly bound to b-lactam
    – this continues activity
27
Q

what are carbapenemases?

A
  • Carbapenems: important class of antibiotics
    – stable to most b-lactamases due to the hydroxyl-containing group
    – active against most clinically relevant bacteria (especially Gram-ve bacteria)
28
Q

what is the real threat to carbapenemases?

A

Real threat from pan-drug resistant G-ve bacteria

29
Q

what does NDM-1 do?

A

NDM-1 hydrolyses and inactivates all b-lactam antibiotics, except aztreonam

30
Q

what should be done for an NDM expressing bacterial infection?

A

– no b-lactam antibiotic can treat
– few, if any, other agents that can treat
– resistant to (almost) all clinical antibacterials
– currently, colistin active against most NDM
-expressing G-ve bacteria
– colistin resistance is increasing
– examples of otherwise healthy (and young) patients dying from a pan
-drug resistant bacterial infection are increasing (very few in UK so far)

31
Q

how do b-lactamase resistant penicillins occur?

A

Steric shields used to block the penicillin derivative from accessing the penicillinase
or β-lactamase active site
* Introduce a bulky group on the side chain

32
Q

how do steric shields work?

A
  • β-lactam ring interacts with both β-lactamase and transpeptidase target enzyme in the
    same way – difficult problem
    – If steric shield is too bulky, then also prevents the penicillin derivative from
    interacting with transpeptidase target enzyme
    – large enough to not react with b-lactamase enzyme
    – small enough to allow reaction with target enzyme
33
Q

what factors affect whether a particular strain is susceptible to a penicillin?

A

– structure
– ability to cross the cell membrane of Gram-negative bacteria
– susceptibility to β-lactamases
– affinity for the transpeptidase target enzyme – rate at which it is pumped back out of cells b

34
Q

how do the hydrophobic groups affect spectrum of activity?

A

– favour activity against G+ve bacteria
– poor activity against G-ve bacteria
– as hydrophobic character increases, little effect on G+ve activity, but drops
against G-ve bacteria

35
Q

how do hydrophilic groups affect spectrum of activity?

A

– little (or reduce) effect on G+ve activity
– increase activity against G-ve bacteria
– enhancement of G-ve activity greatest if hydrophilic group (e.g. NH2, OH,
CO2H) is attached to carbon α to the carbonyl group on side chain

36
Q

give examples of carbapenems/ penems

A
  • Biapenem
  • Doripenem
  • Ertapenem
  • Imipenem
  • Meropenem
    Penems
  • Faropenem
  • Ritipenem
37
Q

what is currently the only monobactam in clinical use?

A

Aztreonam IV use only
strong against gram -ve bacteria
no activity against gram +ve
resistant to many b-lactamase enzymes including NDM
inactivated by extended spectrum b-lactamases and carbapenemases

38
Q

what are b-lactamase inhibitors traditionally based on?

A

b-lactam core

39
Q

what are the properties of sulbactam?

A

Sulbactam – a penam
– not active vs P. aeruginosa or AmpC cephalosporinases – ampicillin and sulbactam (US)

40
Q

what are the properties of tazobactam?

A
  • Tazobactam – a penam
    – used to inhibit ESBL-expressing bacteria in combination with Piperacillin – piperacillin and tazobactam
    – ceftolozane and tazobactam
41
Q

how do b-lactamase inhibitors also attack?

A
  • Are also attacked by b-lactamase enzyme….
    – BUT, form stable covalently bonded complex – enzyme not released to inactivate other b
    -lactams
    – suicide inhibitors of b-lactamase enz
42
Q

what is diazabicycloocyanones?

A

– bicyclic core structure that still reacts at serine of β-lactamases – ceftazidime and avibactam
– imipenem, cilastatin and relebactam

43
Q

what are boronate-based compounds?

A

– boron can adopt a tetrahedral geometry
– interacts at serine of β-lactamases as transition state inhibitor mimicking the
transient tetrahedral species formed during hydrolytic reaction
– meropenem and vaborbacta

44
Q

what is imipenem?

A

– largely excreted unchanged into kidneys
– metabolised by dehydropeptidase-I in kidneys – metabolite is toxic to kidneys

45
Q

what is cilastatin?

A
  • Cilastatin is a dehydropeptidase-I inhibitor – protective to kidneys and works as a booster of imipenem (also boosted with
    relebactam)
46
Q

why do we use prodrugs?

A

Prodrugs used to improve oral stability and uptake
– penicillins particularly acid sensitive, decreased bioavailability
– many zwitterionic / very polar and poor uptake
– ester groups help to increase logP and uptake

MO2 (55 decks)

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