a brief history of antibiotics (co-evolution of antibiotics and their resistance) ?...
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A brief history of antibiotics(co-evolution of antibiotics and their resistance)
?
1940 1950 1960 1970 1980 1990 2000
The Dark Ages(Semmelweis)
Primordial Golden
Pharmacologic
Biochemical GenomicHTS
Target
Disenchantment
(Semmelweis)(again!)
Penicillinasediscovery
Antibiotic resistance plasmids
Increasing Antibiotic Resistance
Transmissiblefluoroquinolone
resistance
FDA Office ofNew Drugs
THE LEAN YEARS
* **
MRSA: UK*, US**Production: 50kg……………………………………………………………………………>106 tons
Side Effects of StreptomycinHeadache
NauseaHearing difficulties, deafness Ringing sensation in the ears
Loss of balanceFatigue
Difficulty in passing urineItchy rashes on the skin
but it cured TB!
Albert Schatz and Selman Waksman Who deserved the Prize?
Fifty years of “Industrial Research” on Antibiotics
EnvironmentalDoubling time:
monthsAeration: low
Nutrients: variableCarbohydrate: limited
Water: variableTemperature: 0-40
pH: 2-10Yield: µgrams
Production
Doubling time: hoursAeration: high
*Nutrients: high and constant
Carbohydrate: highWater: unlimited
Temperature: 25-30pH: 6-7
Yield: grams *Typical substrates for fermentation
Molasses (blackstrap)Fish Meal (herring, anchovy)
Citrus pulpAsparagus juiceCottonseed oil
Malt extractBeef extract Bovine blood
Pork liverDistillers solubles
Hydrolysed rabbit fur
SOME NUMBERS
Number of bacteriophages on Earth 1x1031
Number of bioactive molecules in the Parvome >5x1030
Number of microbes on Earth 5x1030
Number of stars in the Universe 7x1021
Number of humans on Earth 6x109
Number of microbes in all humans 6x1023
Number of human cells in one human 1x1013
Number of microbial cells in one human gut 1x1014
Number of human genes in one human 2.5x104
Number of microbial genes in one human gut 3x106
Combined length of all bacteriophages on Earth 108 Ly
Diameter of the Milky Way 105 Ly
* The US national debt >1x1014
* Number of bubbles in one bottle of Champagne 1x105
(Revised from Kyrpides, 2009)
Origins and Evolution of Bioactive Small Molecules
• Distribution: universal, ancient• Bioactivities: wide range, concentration-dependence• Receptors: mostly macromolecules (cross-species)• Structures: small number of major classes (with
decoration)• Biosynthesis: frequently “assembly line”• Properties and applications: multitudinous
(bio)Chemical Evolution
Hadean Period
LUCA(Last Universal Common Ancestor)
(Modern) Tree of Life
(RNA World)Ribozymes
Meteorites and primordialreactions
“Specialised” Microbial & Plant
MetabolismPrimary Secondary
The Tree of Life
-2.0
-4.0
-0.1
-1.0
-3.0
Origin of Earth (4.5 Billion years)
Last common ancestor
2.3
1.5
1.0
ProteobacteriaCyanobacteria
PlantsDrosophila
Crenarchaeota Euryarchaeota
Gram positivesMouse
0.1
?
3.8
Anoxic(H2, NH3, CO2,)
Chemical evolution/Prebiotic synthesis of biomolecules
Origin of oxygenicphotosynthesis
Increasing [O2]
in atmosphere
Origin of Metazoans20% [O2]
Cambrian Precambrian
Age of Dinosaurs
Origin of Eukaryotes
Origin of Prokaryotes
2.1
Amitochondriate
Bacteria Eukaryotes Archaea
MODULAR ASSEMBLY LINESFOR BIOACTIVE COMPOUNDS
Polyketide synthase
Nonribosomal peptide synthase
Tetracycline, rapamycin, erythromycin
Daptomycin, polymixin, vancomycin
Primordial amino acid components of non-ribosomal peptides
β-alanine, α-aminobutyric acid, β-aminobutyric acid, γ-amino-butyric acid, α-amino-isobutyric acid, α,γ-diaminobutyric acid, α,β-diaminopropionic acid, α-hydroxy-γ-aminobutyric acid, isoserine, N-methylalanine, 3-methylglutamic acid, isovaline, norvaline, sarcosine
etc…
Diketopiperazines: potential catalysts and signals
There are at least three mechanisms for the synthesis of DKPs!
Targets (binding sites) of bioactive small molecules and macromolecular evolution
• Transcription (rifampicin, streptolydigin)• Replication (novobiocin)• *Translation (tetracycline, streptomycin,
chloramphenicol)• Cell wall synthesis (penicillin, vancomycin)• Metabolic pathways (azaserine)
Did bioactive small molecule interactions play roles in the evolution of cellular macromolecules such as ribosomes and polymerases?
Antibiotic Binding Sites (Receptors) on Prokaryote Ribosomes
30S 50S
This 2.5 mD macromolecule is the sensor/receptor for many signals.
A model for the chronological evolution of the ribosome basedon accretion from existing structures.
(Note: no interactions with small molecules!)
Harish and Caetano-Anolles (2012)PLoS ONE 7(3): e32776.doi:10.1371/journal.pone.0032776