Summary
Summary of the synthetic pathways for secondary metabolites (5 pages)
- Course
- Institution
This document summarizes the different pathways for the synthesis of secondary metabolites for the obtainment of novel antibiotics
[Show more]
1 review
By: studyboi098 • 8 months ago
Seller
Follow
edoardocambria
Reviews received
Content preview
NRPSBeta-lactams
- Penicillins (G, Ampicillin, Methicillin): 6-APA (b-lactam ring + thiazolidine ring) + N-acyl
group (R)
Production: Penicillium notatum and chrysogenum (fungi)
100 g/L yield. Addition of precursors inhibit the production BUT
phenylacetic acid increase the production.
Biosynthesis: ACV synthetase + IPN synthase → Penicillin transacetylase → Penicillin G
From Penicillin G → penicillin acylase → 6-APA
MOA: Inhibition of the transpeptidase enzyme in the periplasmatic space. They
mimic the D-Ala-D-Ala terminus (which is the enzyme’s substrate). Active
on gram+.
Resistance: b-lactamases
Natural penicillin, biosynthetic penicillin (precursor directed biosynthesis), semi-synthetic
penicillin (penicillin acylase to remove the phenylacetic acid which is then chemically
replaced)
- Cephalosporins (C, cephalothin, cephamycin): b-lactam ring + diidrothiazinic ring (+ R and
R’)
Production: Acremonium chrysogenum (fungi). 25-35 g/L.
Biosynthesis: ACV synthetase + IPN synthase → Epimerase (aminoadipic acid) →
Expandase → Hydroxylase → Acetyl transferase (+ acetic acid) →
Cephalosporin C
Form Cephalosporin C → D-amino acid oxidase → peroxide
decarboxylation → glutaryl amidase → 7-ACA
MOA: active on gram+ (and gram-). Inhibition of the transpeptidase enzyme.
- Carbapenems (Thienamycin – unstable - , Imipenem): b-lactam ring + five-member ring (S
is replaced with a C)
Production: Streptomyces cattleya (gram+)
Biosynthesis: produced by chemical synthesis
MOA: active against gram+ and gram- (also multi-resistant strains). Inhibition of
the transpeptidase enzyme.
Resistance: drug inactivation (b-lactamases and carbapenemasis), PBP modification,
efflux pump (gram-), permeability barrier (gram-)
- Clavulanic acid: b-lactam ring + five-member ring (S is replaced with a O). Very small
molecule.
Production: Streptomyces clavuligerus (gram+ bacteria)
Biosynthesis: 10-step process (condensation of L-arginine + G3P). Early and late genes.
MOA: Inhibits β-lactamases by covalent binding
, GPAs: heptapeptides (with several aromatic aa → rigid structure) + sugars + Cl atom +
lipid/aromatic
chain
- First generation (Vancomycin, Teicoplanin)
Production: Amycolatopsis orientalis (vancomycin), Actinoplanes teichomyceticus
(teicoplanin) (actinomycetes) (gram+)
For teicoplanin:
Produced only by fermentation → it’s a complex (differences in the lipid
chain).
Addition of valine to obtain the T-A2 molecule.
Biosynthesis: Condensation of proteinogenic and non-proteinogenic, L- and D- amino
acids
MOA: Active only on gram+ (multi-resistant strain - nosocomial infection). They
cover (like a cup) the D-ala-D-ala terminal of the precursor blocking both
transpeptidation and transglycosylation.
Resistance: Modification of the target (D-Ala-D-Ala → D-Lac-D-Ala / D-Ser-D-Ala). Van
genes (vanSR and vanHAX on transposon Tn1546).
- Second generation (Dalbavancin, Oritavancin, Telavancin, A40926)
Synthesis: Semi-synthetic derivatives with a hydrophobic portion.
Lipopeptide antibiotics
- Daptomycin: 13 aa + lipid chain
Production: Streptomyces roseosporus (gram+)
Biosynthesis: 3 proteins comprise the NRPS. The lipid chain is the starter (C domain in
the first module too).
MOA: Against several multi-resistant gram+. The cell membrane is the target (→
possible toxicity). Loss of membrane potential.
- Echinocandins and Pneumocandis: cyclic 6 aa + lipid chain
Production: Fermentation of Aspergillus → biotransformation (deacylation) → chemical
acylation → Echinocandin B
Biosynthesis: The lipid chain is the starter (linoleic acid)
MOA: Fungicidal and fungistatic. Inhibit the β-(1,3) glucan synthesis by blocking
the enzyme.
- Polymyxins: cyclic 7aa + linear tripeptide + lipid chain
Producer: Bacillus polymyxa
MOA: Against carbapenem-resistant gram-. They destabilize the external
membrane (osmotic stress) of gram-negatives by interacting with the LPS.
BUT severe side effects: nephrotoxicity and neurotoxicity.
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller edoardocambria. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $8.39. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
81311 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now