Summary
Summary of the synthetic pathways for secondary metabolites (5 pages)
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This document summarizes the different pathways for the synthesis of secondary metabolites for the obtainment of novel antibiotics
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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.
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