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Thera VII > 09 Beta-Lactams Duncan > Flashcards

09 Beta-Lactams Duncan Flashcards

1
Q

How do host cells destroy bacteria on their own?

A

Host cell brings in O2 – iNOS –> NO, which destroys the bacteria

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2
Q

What is the common pathway shared by all bactericidal antibiotics?

A

Hydroxyl radical. Destroys membranes, proteins, causes cell death

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3
Q

What do bactericidal antibiotics require to work?

A

An intact TCA and electron transport chain in order to make superoxide, which either leads to iron release or H2O2, ultimately leading to the hydroxyl radical

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4
Q

What are some general characteristics of B-Lactams?

A

Disrupt the cell wall of many different types of bacteria. Potent, wide spectrum of activity, low toxicity to humans

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5
Q

What is the general Penicillin Structure?

A

B-Lactam ring. Thiazolidine ring. R group to determine specificity, range

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6
Q

What is required for penicillin biosynthesis?

A

Cysteine and Valine. Penicillin biosynthesis occurs via the action of a Non-Ribosomal Protein Synthetase (NRPS). NRPS produce many of the commonly (therapeutically) used antibiotics

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7
Q

What are the characteristics of the Penicillin R group?

A

R group varies with the producer strain, the growth emdium, or at the hands of the synthetic chemist. In the naturally occuring penicillin, penicillin G, the R group is benzene

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8
Q

What are some different ways to modify the R group?

A

Precursing (putting side chain that you want into a medium and hoping it incorporates). Growth medium (hope to see something you want grows). Synthetic or semi-synthetic. Prototype semi-synthetic penicillins

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9
Q

What are some reasons for changing the R group?

A

Transport properties: interactions with human and bacterial physiology (PepT1 transporter). Interaction with bacterial proteins. Range of species affected. To counteract development of resistance

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10
Q

What are the principals and mechanisms of Drug-Target interactions?

A

Lock (the drug) fits into key (target’s bidning site). Binding affinity can be increased. Binding range can be increased. Binding inhibition can be overcome. ADRs can be minimized

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11
Q

What are the “targeted” R groups in Aminopenecillins to modify binding?

A

Amino side chain preceding benzene; increased G- activity; B-lactamase sensitive; acid stable

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12
Q

What are the “targeted” R groups in Methylpenicillins to modify binding?

A

Methyl group on benzene; resistance to S. aureus B-lactamase; acid labile; 95-98% protein bound

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13
Q

What are the “targeted” R groups in Isoxazolylpenicillins to modify binding?

A

Novel side chain; resistance to lactamase; acid stable; orally active; 95-98% protein bound

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14
Q

What are the “targeted” R groups in Ureidopenicillins to modify binding?

A

Urea group; strain specificity (e.g. Klebsiella, Pseudomonas; B-lactamase sensitive)

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15
Q

What are the “targeted” R groups in Carboxypenicillins to modify binding?

A

Carboxy side chain preceding benzene; strain specificity (e.g. Klebsiella, Pseudomonas; B-lactamase sensitive; ticarcillin gives higher blood levels)

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16
Q

What the the biochemical action of penicillins?

A

Penicillins (and other B-lactams) inhibit the cross-linking of bacterial cell walls

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17
Q

In the peptidoglycan wall, what are the virtical columns made of?

A

Cross bridges of glycine and side chain of L-alanine-D-Isoglutamine-L-Lysine-D-Alanine

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18
Q

In the peptidoglycan wall, what are the horizontal rows made of?

A

N-acetyl-glucosamine and N-acetyl-muramic acid

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19
Q

What are the three stages that cell wall biosynthesis occurs in?

A

1) Sugar precursors made inside the cell. 2) Disaccharide building block made. 3) Disaccharide linked and cross-linked to growing peptidoglycan (where B-lactams act)

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20
Q

How do antibiotic inhibitors of stage 1 (i.e. Fosfomycin) work?

A

Fosfomycin acts as a mimic of PEP (phosphoenolpyruvate (transfers lactic acid to UDP-GluNac)). Recognized by, and inhibits, MurA. Epoxide “O” forms permanent covalent bond with enzyme cysteine

21
Q

What does Transglycosylase do?

A

Moves the immature peptidoglycan from Bactoprenol phosphate and joins it to the other peptidoglycans

22
Q

What does Transpeptidase do?

A

Transpeptidase catalysis of glycine-alanine bond. Creates the mature peptidoglycan

23
Q

What is Penicillins Activity?

A

Penicillins bind to transpeptidase and form a permanent covalent bond, thus inactivating transpeptidase (penicillin is a suicide substrate for transpeptidase)

24
Q

What is Penicillins basis for activity?

A

Penicillins shape “looks like” D-ala-D-ala

25
Q

What are the enzymes inolved in cell wall biosynthesis?

A

Transpeptidase carboxypeptidases. Penicillin-binding proteins (PBPs). Murein hydrolysis. B-lactamases (amidohydrolyases)

26
Q

What activity do PBPs have?

A

Several PBPs, for example PBP1a and PBP2, possess both transglycosylase and transpeptidase activity. Numerous PBPs have been identified; one bacterium will have several types

27
Q

What is the gene structure of PBP1a, 1B, 1C-like genes like?

A
28
Q

What are the various shapes of cell wall?

A

Different extents and types of cross linking in different cell surface regions. Growth and division mean changes in shape occur over time

29
Q

What are the physiological effects of B-lactams?

A

Inhibit cell division. Cause cell lysis. Bacteriocidal

30
Q

What are the mechanisms of sensitivity and resistance?

A

Recognition of PBPs. Accessibility of PBPs (G+ vs. G-). B-lactamses

31
Q

How does the mechanism of “recognition of PBPs” work?

A

Species-specific. Different affinities for different penicillin varieties. ID of good targets: low vs. high molecular weight. Low MW often have only carboxypeptidase activity, and little consequence for pen killing. High MW are multifunctional or multi-protein complexes, often with both TG and TP activity, and are prime pen targets

32
Q

How are the characterizations of PBPs made?

A

In vitro binding, followed by SDS-PAGE to identify which varieties of B-lactam work (bind) best. Identifying useful, and useless, forms of B-lactams to treat an infection

33
Q

How does Methicillin resistance in Staphylococcus occur?

A

Occurs when mutation in MecA gene occurs. MecA encodes a major PBP, PBP2A; mutated version sometimes referred to as PBP2’. Significantly reduces binding affinity for B-lactams (need to develop new varieties of B-lactams that bind to PBP2’)

34
Q

What are the 4 main ways of antibiotic resistance?

A

1) Antibiotic efflux pump. 2) Antibiotic degrading enzyme. 3) Target altering enzyme. 4) Antibiotic altering enzyme

35
Q

What are some general thoughts about resistance?

A

Resistance is bad. Resistance occurs following use of virtually any drug, over time (“Natural” selection for survivors). Two broad categories of resistance (pre-treatment resistance, post-treatment (induced) resistance). Post-treatment “requires” SOS response

36
Q

What can be done in the resistance and the SOS response in order to stop the development of resistance?

A

Can block RecA, causing a cleavage of LexA (which would be used to transcribe error-prone DNA cauesd by DNA damage)

37
Q

What are the characteristics of the SOS response?

A

Initiated by DNA damage: a repair system. Usually entails new DNA synthesis. Induces novel, error-prone DNA polymerases. Error-prone DNA synthesis (more proteins with mutations –> some selectivity advantageous –> resistance). Also reduces growth rate (to allow time for repair). Antibiotic effectiveness is reduced proportional to growth rate (most obvious for B-lactams, where changing cell wall is required for growth)

38
Q

What are Amidohydrolase and penicillinase?

A

B-lactamses in bacteria. Penicillinase acts very similarly to transpeptidase (binds to B-lactam, cleaves B-lactam ring). The difference is, instead of forming a permanent covalent bond, the enzyme dissociates and then can do it all over again and again. Amidohydrolase cleaves the R group

39
Q

What are the different classes of B-lactamases?

A

TEM and SHV. Extended Spectrum B-lactamases (ESBLs). AmpC or C class

40
Q

What are TEM and SHV?

A

“Earliest variety; lowest range of activity. Multiple forms of each type exist; different genes

41
Q

What are Extended Spectrum B-lactamases (ESBLs)?

A

Active against a wider range of B-lactams: can degrade 3rd generation cephs and monobactams

42
Q

What are AmpC or C Class?

A

Initially chromosomal, inducible. Now plasmid encoded; rapid & easy transmission. Not inhibited by clavulanate, sulbactam, tazobactam

43
Q

How do humans counterattack B-lactamases?

A

Clavam (oxygen in the 5 atom ring). Binds to B-lactamase, and blocks its activity. Humans got this with a little help from our “friends”, in this case a type of fungi

44
Q

What are Tazobactam and Sulbactam?

A

B-lactamase inhibitors

45
Q

What is the basic structure of Cephalosporins?

A
46
Q

What are the characteristics of the different generation CEPHs?

A

1st: the original isolate, and forms with equivalent activity. 2nd: increased activity against certain kinds of microorganisms. 3rd: activity against resistant microorganisms. 4th: newer. 5th: newest

47
Q

What is sensitivity and resistance to CEPHs like?

A

Basically, same considerations as described for the penicillins apply. B-lactamses cleave CEPHs; sometimes termed cephalosporinases. Resistance can arise through evolutoin or obtaining these B-lactamases; sensitivity can be re-established through modifications in the side chains that prevent B-lactamase activity

48
Q

What are carbapenems?

A

B-lactam class. Most active of the anti-microbial B-lactams. Most resistant to degradation by “-ases”. Avoids resistance. Combined with cilastatin to reduce renal metabolism. Double bond in 5 membered ring makes these penems rather than penams

49
Q

What is Aztreonam (Azactam)?

A

B-lactam. A semi-synthetic monobactam with high activity against gram negative bacteria, and high resistance to common B-lactamases; not recognized as “penicillin” by allergic system

Thera VII (37 decks)

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