Lecture 6 - Med Chem Antibiotics 1 Flashcards
Antimicrobial agents are….
synthetic substances that are unrelated to natural products but still inhibit or kill microorganisms
Broad Spectrum activity is….
wide range of bacteria
Narrow Spectrum activity is…
limited subset of bacteria
Bacteriostatic is…
stop bacteria from multiplying
Bactericidal will….
kill bacteria
Antibiotics are….
microbial metabolites or synthetic analogs inspired by them that, in small doses, inhibit the growth and survival of microorganisms without serious toxicity to the host.
Beta Lactam Antibiotics….
Penicillins Cephalosporins (1-4th gen) Carbapenems ( imipenem + meropenem) Monobactam ( aztreonvam) Glycopeptides (vancomycin + teicoplanin)
Penicillin….
natural penicillins
Anti-staphylococcal
Aminopenicillins
Anti-pseudomonas penicillins
Gram (-) bacterial membrane structure
2 membranes
Out membrane functions as efficient permeability barrier containing LPS + Porins
Peptidoglycan (murrain) polymer consisting of sugar + amino acids that forms mesh-like layer outside the plasma membrane
PBP
Penicillin Binding Protein
Site of Penicillin Action
Gram (+) bacterial membrane structure
simpler than that of Gram (-)
lipid billayer cell membrane of most + bacteria is covered by a porous peptidoglycan layer
Beta-lactamases are secreted outside the gram + cell and must be replenished frequently
Lactam =
Cyclic amide
B- Lactam =
Cyclic amide w/ 4 atoms in its ring
Penam =
4 atom cyclic amide
S at 4
no double bond 2-3
Penem
4 atom cyclic amide
S at 4
double bond 2-3
Carbapenem
4 atom cyclic amide
No S in other ring
Double bond 2-3
Cefam
4 atom cyclic amide
S is at 5**
Double bond at 2-3
Monobactam
4 atom cyclic amide
Beta-lactam info
called beta- because cyclic addition occurs between b position and NH
have strain, generally not stable, water will hydrolyze
Why don’t you want to store beta-lactams in metal container?
easily hydrolyzed by water or other metal ions
store in glass or plastic
Fermentation-Derived Penicillins
Original Fermentation derived penicillin were produced by Penicillium chrysogenum
During fermentation, if sufficient supply of phenyl acetic acid you produce mainly….
Benzylpenicillin
Penicillin G
During fermentation, if sufficient supply of Phenoxyacetic acid you produce mainly…
Phenoxymethylpenicillin
Penicillin V
during fermentation, exclusion of side chain precursor acids leads to production of….
6-APA
6-aminopenicillinic acid
** Has very weak antibiotic activity **
6-aminopenicillinic acid. has addition of what at C6 of Penam…..
H2N, nothing extra
Penicillin V has addition of what at C6 of Penam….
H2N, connected double bond O - C - 6 C ring with double bonds
Clinically relevant degradation reactions of Penicillins?
- most unstable bond in the penicillin molecule is the highly strained and reactive B-lactam amide bond
- Slow cleavage in water unless heated; rapid cleavage in acidic and basic media
What controls the nature of Hydrolysis of Penicillins?
The nature of R group added to N2H off of C6
Penicillin G has addition of what at C6 of Penam….
H2N, connected to double bond O, C - O - 6 C ring with double bonds
Why do penicillins bind to PBPs?
Beta-lactam resembles the amnio acid it needs to build ALA structure, by mistake it takes up Beta-lactams which will cause the PBP to lock and it won’t be able to construct the way.
Need to protect B-lactam bond from acid so that it still retains this activity
Beta-lactamases are what chops this bond
how to protect penicillins in part from acid degradation?
adding side chain R group (Benzyl or phenoxymethyl) which is EWG, decrease electron density on the side chain carbonyl
Oral survival of Benzylpenicillin (G) vs phenoxymethyl penicillin (V)
G = 15-30% survives V = 60-73% survives
As lipophilicity of side chain of penicillin increases, serum protein binding of antibiotic will…
increase
This leads to partial protection from degradation but it does not reduce effective bactericidal conc of the drug
degree of serum protein binding of penicillins has how much influence upon their half-lines?
little
Penicillins + Beta-lactam MOA
- Closely resemble geometry of acylated D-ala-D-ala (cell wall segment)
- PBP mistakenly accepts it as a normal substrate
- This leads to selective and irreversible inhibition of PBP enzyme
- This result in structurally weak cell wall, subject to osmotic stress. Cell lysis can result and cell rapidly dies
EDG vs EWG R group on hydrolysis
EDG= More hydrolysis EWG = Slower Hydrolysis
B-lactamases are…
enzymes (serine proteases) elaborated by microorganisms that catalyze hydrolysis of the b-lactam bond and inactive b-lactam antibiotics to penicillin acids before they can reach PBPs
What allows B-lactamases to turn over many times and allows for a comparatively small amount of enzyme to destroy a large amount of drug?
Hyrdolytic regenerations of the active site are more facile than with the cell wall transamidase
B-lactamases in Gram +
ie Staphylococci
B-lactamases are shed continuously into the medium and meet the drug outside the cell wall
B-lactamases in Gram -
Secreted into periplasmic space between inner/outer membrane, they dont readily escape into medium and need no be resynthasized
How do drugs try to reduce being attacked by B-lactamases?
By creating steric hinderance protecting the bond that B-lactamases attacks
Semi-synthetic Penicillins
Structural modifications made to the side chain of penicillin nucleus in an effort to improve oral bioavailability, improve stability to B-lactamase activity, and inc spectrum of action
Anti-staphylococcal (Penicillinase-Resistant) Penicillins
Methicillin ( 2 OMe)
Nafcillin
Resistance to enzyme degradation based on steric hinderance
OMe group is EWG by inductive, EDG by resonance. resonance donating effect is stronger
Why is Methicillin unstable to gastric acid?
Due to donating effect of OMe
Methicillin vs nafcillin resistance to B-lactamase?
Nacficllin»_space; due to more bulk/steric hinderance
Narrow Spectrum Penicillinase-Resistant Oral Penicillins due to
- Resistance to enzyme degradation based on steric hindrance and stability to acid hydrolysis through chemical modification
- Replacement of phenyl ring with isometric isoxazolyl ring substituted with methyl and phenyl groups
Isoxazolyl ring is….
electrons withdrawing, leads to improved stability of lactase ring to acid hydrolysis
Narrow Spectrum Penicillinase-Resistant Oral penicillins examples
Oxacillin
Dicloxacillin = 2 Cl groups on ring
Flucloxacillin
-Cloxacillin = only 1 chloro group on ring
Cloxacillin vs Dicloxacillin oral bioavailability and renal elim
Cloxacillin = 36.9% bioavailability, 33min renal elim
Dicloxacillin = 48.8% bioavailability, 42min renal elim
More Cl = more lipophilic = inc half life
Broad Spectrum Penicillinase-Sensitive Oral Penicillins
Aminopenicillins
Aminopenicillins info
- replace H of side chain ethylene w/ primary amino group
- EW amino group in protonated form improves stability of lactam ring towards acid hydrolysis = makes orally active
- Broad spectrum, sensitivity to (-) due to greater pen of ampicillin into gram (-) bacteria)
Aminopenicillins lack…..
stability towards B-lactamases, add Clavulanic acid (a mold product) which has weak antibacterial activity but has excellent irreversible inhibition of most b-lactamases
** can also add sulbactam, oxidation of sulphur atom to sulfone greatly enhances potency of sulbactam ***
Speculative Mechanism for irreversible inactivation of B-lactamases by clavulanic acid and sulbactam
b-lactamase will attack Clavulanic acid or Sulbactam and it will bind forming a complex and gets stuck
Enhancement of Ampicillin’s Oral Bioavalibility through prodrug formation
Ampicillin well absorbed, oral efficacy for systemic infection can be enhanced through prep of prodrug
Bacampicillin = weak base, rapidly/well absorbed in duodenum and quickly cleaved by serum esterase’s to bioactive ampicillin
Penicillinase-sensitive, broad-spectrum, parenteral penicillins
Piperacillin
Azlocillin
Mezlocillin
Also known as Acylureidopenicillins
Acylureidopenicillins info
preserve Gram + activity, but have higher Gram - potency
oral stability gone because -NH2 group no more basic after structural modifications
Ticarcillin info
A carboxypenicllin and used in combo w/ clavulanate a Timentin
Not well absorbed orally, given IV or IM
Cephalosporin info
- 1st isolated from cultures of Cephalosporium acremonium from sewer in Sardinia in 1948
- Degradation of side chan by chemical means produces 7-ACA
- Modification of 7-ACA side chain resulted in development of useful antibiotic agents
- Allergenicity is less commonly experienced and is less severe with cephalosporins than with penicillins
Cephalosporins vs penicillin structure
cephalosporins have b-lactam ring attached to 6 member ring, penicillins have attached to 5 member ring
this makes them less strained and less reactive/potent
What makes up reactivity loss in Cephalosporins?
- possession of olefinic linkage at C-2,3
- methyleneacetoxy group at C3
this reduces energy required for b-lactam ring to be opened by hydrolysis
What modulates the facility with which the B-lactam bond of the Cephalosporins is broken?
nature of C-7 substituent
nature of C-3 substituting + its ability to carry away neg charge
Cephalosporin MOA
bacterial and have the same mode of action as other b-lactam antibiotics such as penicillins
Cephalosporin Metabolism
Active -> (esterase) = much less active -> (spontaneous lactonization) = Inactive
1st gen Cephalosporins
good activity against + but less against -
most + cocci are susceptible (not including enterococci + MR staph)
Oral 1st gen
Cephalexin
Cefadroxil
Cephalothin
Parenteral 1st gen
Cephazolin
Cephradine
Cephradine
Interesting drug design, Partial hydrogenation (Bird reduction) of the aromatic ring - No conjugated olefinic
Comparatively acid stable and hence rapidly and near completely absorbed from GI
Can be used both orally and IM
How to tell if 1st gen cephalosporin will have metabolic inactivation
- CH3 off C3 = no, maintain potency
- Ester off C3 = yes
2nd gen cephalosporin agents
grater - activity while retaining gram + cocci activiy
more resistant to beta-lactamase
Oral 2nd gen
Cefaclor
Cefuroxime xetil
Parenteral 2nd gen
Cefamandole ( improve activity against H. influenzae)
Cefonicid ( long 1/2 life)
Cefuroxime
Cefoxitin ( anaerobic coverage for B. fragilis)
How does 2nd gen bring stability to B-lactamases?
Target C7 ( OMe = steric hinderance) or C3 sites (Cl = EWG = helping with opening but not good leading group)
3rd gen cephalosporin agents
broad spectrum of activity and further inc activity against gram -
those in oral form + those w/ anti-pseudomonas activity have decreased activity against gram + organisms
Oral 3rd gen
Ceftibuten
Parenteral 3rd gen
Cefotaxime ( Good gram +, excellent CNS pen)
Cefoperazone (antipseudomonal, dec gram +)
Ceftazidime (antipseudomonal, dec gram +)
Ceftriaxone (long T1/2, excellent CNS pen)
Syn- vs Anti- configuration for activity in 3rd gen cephalosporins
Syn = better hinderance, closer to amide
better b-lactam stability
4th gen Cephalosporins
extended spectrum agents w/ similar gram + activity as 1st gen
greater resistance to beta-lactamases than 3rd gens
can cross BBB ( CSF ~ 10%) and are effective in meningitis
Also used against Pseudomonas aeruginosa and post operative intracranial infection
4th gen cepahlosporin is…
Cefepime
Modification of cefepime
N-Methylpyrrolidine group at C3
increases penetration into gram - bacteria
Carbapenems
- kill bacteria by bing to PBP and inhibit cell wall synthesis
- exhibit broad spectrum of activity compared to cephalosporins + penicillin, effectiveness less affected by B-lactam resistance
- sulfor atom not part of 5-member ring but replaced with methylene at that position
- Sulfor atom attached at C3 as part of functionalized side chain. Endocylcic olefinic linkage enhances reactivity of B-lactam ring
1st carbapenem isolated
thienamycin, from Streptomycin Cattleya
unstable in aqueous solution so impractical to admin to patients.
self inactivating due to primary -NH2
Imipenem basic info + how it was made
IV not Oral
terminal amino group at C3 attacks b-lactam bond of nearby molecule and destroy activity
problem solved by changing amino to less nucleophilic N-formiminoyl moiety to make Imipenem ***
Imipenem info
penetrates well through porins and very stable, even inhibitory to many B-lactamases
Not orally bioactive
given w/ Cilastatin to protect it from Renal Dehydropeptidase which hydrolyses it through B-lactam bond
Meropenem info
Addition of chiral methyl group at C4 = intrinsic resistance to hydrolysis by dehydropeptidase-1 so it can be admin alone
common SE similar to imipenem/cilastatin but less serious
Aztreonam info
totally synthetic parenteral antibiotic whose antimicrobial spectrum is devoted almost exclusively to gram - microorganism and is capable of inactivating some b lactamases
similar MOA to penicillins, etc
sulfuric acid moiety strong EWG, makes bond more susceptible to hydrolysis
Glycopeptide Antibiotics info
- inhibit cell wall synthesis by inhibiting peptidoglycan synthesis
- bind to acyl-D-alanyl-D-alanine in peptidoglycan
effective primary against gram + cocci
Vancomycin info
large, hydrophilic
not absorbed from intestine, poor oral bioavailability
must be given IV for systemic therapy
Teicoplanin
Semisynthetic glycopeptide, similar spectrum of activity to Vanco
treatment of serious infections by Gram +, MRSA
mixture of several compounds
50X-100X more lipophilic than vancomycin
increased 1/2 life, better tissue pen
2-4x more active than vanco
more acidic, so can be given IV
