Lecture 20, 21, and 22 Flashcards
What is the largest class of beta lactam antibiotics?
Cephalosporins
Cephalosporin ring structure is more ___ stable
Acid
Are cephalosporins susceptible to acid hydrolysis in the gut?
Yes, just not as much as penicillins
How are cephalosporins administered?
Many are IV only, but some oral forms also exist
Why are some cephalosporins IV only?
Very hydrophilic w/ many H-bond donors and acceptors, and may even be charged; this breaks Lipinski’s rules
Are cephalosporins more or less broad spectrum than penicillins?
More broad spectrum
What are cephalosporins effective against that penicillins aren’t?
Many gram neg species and more anaerobes
Why are cephalosporins more stable than penicillins?
Beta lactam ring strain is much lower
Describe the reactive carbonyl of cephalosporins
Like penicillins, the beta lactam carbonyl carbon of cephalosporins is more electrophilic than a typical amine due to lack of resonance
Which area of cephalosporins can be involved in causing beta lactam ring opening?
Side chain amide
How can oral absorption of cephalosporins be increased?
Using the same strategies to engineer acid resistance in penicillins
Cephalosporins are ___ resistant to beta lactamases than pencillins
More (making them broader spectrum)
Which isomer form shoud the oxime group on the R2 (alpha carbon) be in for a cephalosporin?
Cis (only this isomer confers beta lactamase resistance; trans isomer has no effect on beta lactamase activity important)
Cephalosporins that cover pseudomonas and MSSA are ___ gen
4th
Do cephalosporins cover MRSA?
Nope (except a few)
What makes cephalexin orally active?
- EW R2 amino group
- Methyl group on position 3 is hydrophobic, which increases oral absorption but also reduces potency
What is the spectrum of cephalexin?
- Gram pos (strep species, MSSA)
- Gram neg (E coli, klebsiella)
- Few anaerobes
What makes cefaclor orally active?
- EW (NH2) R2 group
- Position 3 Cl (increases potency and doesn’t increase hydrophilicity, so has good oral absorption)
What is the spectrum of cefaclor and cefprozil?
- Gram pos (strep species, MSSA)
- Gram neg (E coli and klebsiella)
- H. influenza and N. meningitidis
- Some anaerobes
What makes cefprozil orally active?
- EW R2 group
- Tyrosine-like group that increases absorption likely by AA transport
- Position 3 hydrophobic group
What makes cefuroxime axetil more potent than cephalexin? What is a downside to this difference?
- Position 3 group is EW
- This group is a substrate for esterases (converts inactive form to active form, but also converts active form to a much less active form)
What is the spectrum of cefuroxime axetil?
- Gram pos (strep species, MSSA)
- Gram neg is broader than cefaclor
- Some anaerobes
What is cefufroxime axetil used to treat?
Non-hospital acquired strep pneumoniae
For cephalosporins, are position 3 groups that are EW and hydrophobic more or less potent compared to EW hydrophilic groups?
Hydrophobic = less potent
What is the spectrum of cefixime?
- Gram pos (strep species)
- Gram neg (E coli, Klebsiella)
- H. influenza and N. meningitidis
- Not MSSA
What is cefixime used for?
Pediatric UTI’s
What is cefazolin used for?
As a surgical antibiotic given 1 hour prior to start and infused during
What makes cefoxitin resistant to beta lactamase?
Methoxy group, but this also reduces potency
What is the spectrum of cefoxitin?
- Gram pos (strep species, MSSA)
- Many gram neg
- Many anaerobes
What is important to note about the strong EW X group of cefoxitin?
- Potent
- No oral absorption
- Susceptible to hydrolysis and spontaneous lactone formation, so shortens t 1/2
What makes ceftriaxone resistant to beta lactamase?
Oxime structure
What is the spectrum of ceftriaxone?
- Most gram pos except MRSA
- Most gram neg
- Most anaerobes
What is ceftriaxone used to treat?
Meningitis
What makes ceftazidime and cefepime resistant to beta lactamase?
Bulky oxime structure
What is the spectrum of ceftazidime and cefepime?
- Most gram pos except MRSA
- Most gram neg
- Most anaerobes
- Effective anti-pseudomonal
What is cefepime used to treat?
Skin infections, abdominal infections, and pneumonia
What is the spectrum of cefetecol?
- Activity against many gram pos and gram neg
- Anti-pseudomonal
What do all beta lactamase inhibitors have the potential to do?
Irreversibly covalently modify beta lactamase
What is the benefit to administering beta lactams w/ beta lactamase inhibitors?
Protects beta lactam from hydrolysis by beta lactamase, which widens the spectrum of the beta lactam
How can you make a beta lactam cover MSSA that normally doesn’t cover it?
Administer beta lactam w/ beta lactamase inhibitor
What are some beta lactamase inhibitors?
- Clavulanic acid
- Sulbactam
- Tazobactam
Which ring structure is the most strained of the beta lactams?
Carbapenem
What are characteristics of carbapenems?
- Extremely potent and very broad spectrum
- Not orally active, IV only
- Rapidly metabolized (some metabolized by dehydropeptidase 1 in the kidney)
- Chemically unstable
What makes imipenem susceptible to hydrolysis by dehydropeptidase 1 and how can this be avoided?
- No R2 substitution
- Can be administered in combination w/ cilastatin, which inhibits dehydropeptidase 1
Do carbapenems work against MRSA?
Never
What is the spectrum of imipenem and meropenem?
- Most gram pos, except MRSA
- Most gram neg, even pseudomonas species (so is an anti-pseudomonal)
- Most anaerobes
- Meropenem has slightly narrower spectrum, but much higher stability
What is panipenem used in combination w/ and why?
Betamipron to inhibit dehydropeptidase 1
What is significant about doripenem?
- Supposedly better anti-pseudomonal than meropenem
- More chemically stable than imipenem
- Resistant to dehydropeptidase 1 like meropenem
Which carbapenem is not an anti-pseudomonal?
Ertapenem
Why is MRSA resistant to many antibiotics?
Has beta lactamase, but main reason is presence of special penicillin binding protein PBP 2a
What does PBP 2a have affinity for?
All penicillins, carbapenems, and almost all cephalosporins; these are all the organisms MRSA is resistant to
How do antibiotics minimize toxicity to host and maximize toxicity to microorganisms?
By targeting metabolic processes that are particular to microorganisms and significantly different from those that happen in human cells
Why are most viral infections difficult to treat?
Viruses mostly exploit host metabolic processes in order to proliferate
What is a plasmid?
Circular DNA that can be shared among bacteria and often cary antibiotic-resistant genes
Is the protein synthesis machinery of bacterium the same as in humans?
No
How many of the subunits of a ribosome differ btwn bacterium and humans?
Both
What is different about the RNA in bacterium compared to humans?
In bacteria, there is no 5’ methyl guanine cap, so it is not spliced
What is different about transcription btwn bacteria and humans?
In bacteria, RNA polymerase and other aspects of transcription are different (no introns and no splicing)
Which enzymes involved in DNA synthesis are different btwn bacteria and humans?
DNA polymerase, DNA gyrase, and topoisomerase
Why do bacteria, yeast, and other single-celled organisms have cell walls?
Have high concentrations of osmotically active components (proteins, DNA, RNA, carbs) while environment has low concentrations, so this produces huge osmotic pressure across the cell membrane
What do porins do?
- Hydrophilic channel, so some antibiotics can travel through this channel
- Bacteria w/ less porins = less susceptibility to those antibiotics
What are penicillin binding proteins involved in?
Peptidoglycan synthesis
What is the function of teichoic acids?
Increase strength of GM+ cell walls; can be bound to lipid bilayer or peptidoglycan
Which 3 characteristics determine what antibiotic therapy should be started?
1) Is the bacteria sensitive or resistant to the antibiotic in question? (usually don’t have this info)
2) Is the bacterium GM+ or GM-; could be neither (mycoplasma pneumonia or mycobacterium tuberculosis or leprae)
3) Is the organism anaerobic?
What is the most common cause of impetigo?
Streptococcus pyogenes, but also Staph aureus
What is the most common cause of acute cellulitis?
Strep pyogenes
What is the most common cause of necrotizing fasciitis?
Strep pyogenes
What is the most common cause of folliculitis?
Staph aureus, sometimes pseudomonas aeruginosa
What is the most common cause of furuncles (boils)?
Staph aureus
What is the most common cause of carbuncle?
Staph aureus
Which organism is the major cause of hospital acquired infections?
Pseudomonas aeruginosa
What can pseudomonas aeruginosa cause?
- Pneumonia
- Sepsis (bacteremia)
- Skin and soft tissue infection
- UTI’s
Which bacteria have porins?
Only GM-
Which bacteria have beta-lactamase?
GM+ and GM-
Which bacteria have penicillin binding proteins?
GM+ and GM-
Which bacteria have teichoic acids?
GM+
What makes pseudomonas aeruginosa difficult to treat?
Porins channels are difficult to penetrate, and also has fewer porin channels in general
What are the most common causes of community-acquired pneumonia?
- Haemophilus influenzae (GM-)
- Strep pneumoniae (GM+)
- Moraxella catarrhalis (GM-)
- Atypical pneumonia caused by mycoplasma pneumoniae (*more common) or legionella pneumophila (most common pneumonia seen in community)
What is mycoplasma pneumoniae?
- Parasite of respiratory tract
- Binds to receptors on tracheal epithelium
- Extracellular and intracellular pathogen
What is NAM attached to in peptidoglycan?
- To unnatural peptide L-Ala-D-Glu-L-Lys-D-Ala
- COOH of NAM connects to peptide via N-alpha amide bond
How are adjacent strands of amino sugars attached in peptidoglycan?
5x Gly crosslinks adjacent strands via L-Lys and D-Ala (results in L-Lys-Gly-Gly-Gly-Gly-Gly-D-Ala); attached via peptide bonds
What is Parks nucleotide?
UDP-NAM-L-Ala-D-Glu-L-Lys-D-Ala-D-Ala
What is transglycosidation and what catalyzes this process?
- Attaches NAG to NAM
- Catalyzed by transglycosidase
What is transpeptidation and what catalyzes this process?
- Connects Gly chain to D-Ala
- Catalyzed by transpeptidase (a penicillin binding protein)
What digests amino sugar linages?
Lysozyme
What is the first step of natural cell wall degradation catalyzed by?
Lytic transglycosylases
How do penicillins work?
- By covalently binding to penicillin binding protein transpeptidase b/c it “looks” like terminal D-Ala-D-Ala of peptidoglycan
- Active site Ser reacts w/ the highly strained lactam ring causing the ring to open and form a covalent enzyme intermediate => almost permanent covalent alkylation of transpeptidase enzyme
Penicillin is considered a ____ inhibitor of transpeptidase
Covalent non-competitive
What makes a beta-lactam ring more susceptible to hydrolysis than an amide bond?
- Amide bonds can undergo resonance, which decreases electrophilicity of carbonyl carbon; beta lactam ring can’t undergo resonance
- S and N help to withdraw electrons from the carbonyl, further increasing the electrophilic nature of the carbonyl
What is the cause of MRSA’a resistance to nearly all beta-lactam antibiotics?
Penicillin binding protein 2A
What are some narrow spectrum beta-lactamase sensitive penicillins and what are they used for?
- Pen G and Pen V
- Used for strep GM+ (except MSSA and MRSA) and some anaerobes (esp. oral anaerobes)
What are some narrow spectrum beta-lactamase resistant penicillins and what are they used for?
- Methicillin, nafcillin, cloxacillin, and dicloxacillin
- GM+ staph aurues (MSSA) but not MRSA
What are some broad spectrum beta-lactamase sensitive aminopenicillins and what are they used for?
- Ampicillin and amoxicillin
- Many GM+, some GM- (haemophilus influenzae, neisseria meningitidis, E. coli), and some anaerobes
What are some broad and extended spectrum beta lactamase sensitive anti-pseudomonals and what are they used for?
- Ticarcillin and piperacillin
- Many GM+ (except MSSA and MRSA), pseudomonas aeruginosa, some anaerobes, and many GM-
What does the acid instability of beta lactams cause?
- Basically no oral absorption (other reasons for no oral absorption also)
- High amounts of penicillin allergies
How is the beta lactam ring strain relieved?
Opening the ring (acid or base catalyzed; also catalyzed by beta lactamases)
What effect does the acyl side chain have on the beta lactam ring?
- Produces a resonance structure that places a negative charge on the side chain carbonyl O, which makes it a better nucleophile
- The side chain carbonyl O attacks the beta lactam carbonyl, which is particularly reactive => beta lactam ring opening
What effect does an EW R group have on a beta lactam antibiotic?
- Decreases attack on the beta lactam carbonyl, producing less ring opening
- Confers acid stability
What is significant about penicillamine?
Reactive and involved in penicillin allergy
What is significant about penillic acid?
- Can be formed in gut after oral dosing
- Happens readily w/ Pen G and methicillin, but not w/ amoxicillin or Pen V
What is significant about penicillenic acid?
- Can be formed easily over a wide pH range
- Usually always some present in penicillin
- Very reactive and involved in allergies to penicillin
Which compounds promote penicillin allergies that are not anaphylactic?
Penicilloic acid and penicillenic acid
Why should expired pencillins never be used?
Penicilloic acid and penicillenic acid can naturally accumulate in penicillin powder or in liquid formulations, so this promotes the development of penicillin allergies
Which compound promotes anaphylactic penicillin allergies?
Penicillamine
Which penicillins are acid stable? What does this mean?
- Pen V, ampicillin, amoxicillin
- Orally active
Do acid resistant penicillins have less incidence of allergy?
No
Why is amoxicillin used more often than ampicillin?
Less side effects
What are the 4 methods that bacteria develop resistance to beta lactams?
- Increased production of PBP transpeptidase
- Mutation of PBP transpeptidase that reduces affinity for penicillin (specifically PBP 2a)
- Transport of penicillin across outer membrane
- Production of beta lactamases
What do the 4 classes of beta lactamases differ in?
- Structure and mechanism
- Resistance to inhibitors of beta lactamases
- Spectrum of activity (types of beta lactams hydrolyzed)
- Organisms that produce these beta lactamases
Where are beta lactamases secreted?
Into the medium that the bacteria are growing in, so beta lactams are digested in the medium before they reach the bacterium
What is the rate limiting step for beta lactamases?
Collision of the enzyme w/ beta lactams
What is a part of all beta lactamase resistant penicillins?
Aromatic substituent
What is the spectrum of cloxacillin?
- Staph aureus (MSSA)
- Staph epidermidis
- Strep pyogenes (all GM+)
- Covers most skin pathogens, so can be used empirically to treat skin infections where MRSA is not suspected
- No activity against GM-
What is the spectrum of amoxicillin?
- GM+ = strep pyogenes, strep pneumoniae, and staph epidermidis
- Not MSSA or MRSA
- GM- = E coli, H influenza, N meningitidis, some salmonella, and shigella species
- Some anaerobes
What is a good antibiotic for neonates and children and why?
- Amoxicillin
- Has activity against many of the most common and serious childhood pathogens
What makes pseudomonas resistant to beta lactams?
- Low uptake
- Some strains produce beta lactamases
How can an antibiotic cross the outer membrane of Pseudomonas aeruginosa and other GM- organisms?
- Through the porin
- Trick an active transporter to take it up into the bacterium
How can a beta lactam be modified to pass through the porin of a GM- bacteria?
Make the R group very hydrophilic (ex: COOH or ureido group) since the porin is an aqueous channel
What do bacteria need from the environment and how do they get it?
- Need iron from the environment
- Use short peptides call siderophores to chelate iron, and then a special set of active transporters take up the iron-siderophore complex
How can an anti-pseudomonal trick an active transporter to take it up into the bacterium?
Catechol-substituted cephalosporins have an R group that mimics the catechol structure of siderophores
What is ticarcillin and what is it normally given w/ and why?
- Anti-pseudomonal
- Given w/ clavulanic acid b/c it is beta lactamase sensitive
What is the activity of ticarcillin?
- Pseudomonas aeruginosa
- Most GM- and many GM+ (except staph aureus)
- Many anaerobic bacteria
Is ticarcillin or piparcillin more broad spectrum against GM-?
Piparcillin
All cephalosporins are based on the structure of _____
Cephalosporin C
How do cephalosporins differ from penicillins w/ respect to activity?
Cephalosporins have increase GM- activity and similar GM+ activity, so are more broad spectrum
What effect do cephalosporins have on transpeptidase enzymes?
Nearly permanently inactivate them
What is important about the fact that beta lactams almost permanently covalently modify PBP transpeptidase enzymes?
This causes a post-antibiotic effect (there is still activity of penicillins even after 5x their half-life)
