A brief history of antibiotics
(co-evolution of antibiotics and their resistance)
Penicillinase
discovery
Antibiotic resistance plasmids
THE LEAN YEARS
?
Increasing Antibiotic Resistance
*
1940
Primordial
The Dark Ages
(Semmelweis)
Transmissible
fluoroquinolone
resistance
1950
Golden
**
1960
1970
1980
Biochemical
Target
Pharmacologic
FDA Office of
New Drugs
1990
2000
Genomic
HTS
Disenchantment
(Semmelweis)
(again!)
MRSA: UK*, US**
Production: 50kg……………………………………………………………………………>106 tons
Side Effects of Streptomycin
Headache
Nausea
Hearing difficulties, deafness
Ringing sensation in the ears
Loss of balance
Fatigue
Difficulty in passing urine
Itchy rashes on the skin
but it cured TB!
Albert Schatz
and Selman Waksman
Who deserved the Prize?
Fifty years of “Industrial Research” on Antibiotics
Environmental
Doubling time:
months
Aeration: low
Nutrients: variable
Carbohydrate: limited
Water: variable
Temperature: 0-40
pH: 2-10
Yield: µgrams
Production
Doubling time: hours
Aeration: high
*Nutrients: high and
constant
Carbohydrate: high
Water: unlimited
Temperature: 25-30
pH: 6-7
Yield: grams
*Typical substrates for fermentation
Molasses (blackstrap)
Fish Meal (herring, anchovy)
Citrus pulp
Asparagus juice
Cottonseed oil
Malt extract
Beef extract
Bovine blood
Pork liver
Distillers solubles
Hydrolysed rabbit fur
SOME NUMBERS
(Revised from Kyrpides, 2009)
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
Inter-Kingdom Signalling
The Parvome
(Rumbaugh, 2007)
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
The Ages of Planet Earth
(bio)Chemical Evolution
Hadean Period
(RNA World)
Ribozymes
Meteorites and
primordial
reactions
LUCA
(Last Universal Common Ancestor)
“Specialised”
Microbial & Plant
Metabolism
Primary
Secondary
(Modern) Tree of Life
The Tree of Life
Bacteria
-0.1
Eukaryotes
Archaea
Mouse Amitochondriate Crenarchaeota
Gram positives Proteobacteria
Plants
Euryarchaeota
Cyanobacteria
0.1 Drosophila
Age of Dinosaurs
Cambrian
Precambrian
20% [O2]
-1.0
1.0
Origin of Metazoans
Origin of Eukaryotes
1.5
Increasing
[O2]
in atmosphere
2.1
-2.0
2.3
Origin of oxygenic
photosynthesis
?
-3.0
Anoxic
(H2, NH3, CO2,)
-4.0
Origin of Prokaryotes
Origin of Earth (4.5 Billion years)
3.8
Last common ancestor
Chemical evolution/
Prebiotic synthesis of biomolecules
Aminoglycoside biosynthesis in a streptomycete
MODULAR ASSEMBLY LINES
FOR BIOACTIVE COMPOUNDS
Polyketide synthase
Tetracycline, rapamycin, erythromycin
Nonribosomal peptide synthase
Daptomycin, polymixin, vancomycin
Carbonaceous meteorites
as sources of
chemical intermediates
Pizzarello & Shock (2010)
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,βdiaminopropionic acid, α-hydroxy-γ-aminobutyric acid, isoserine, Nmethylalanine, 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 based
on 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
KEEP CLEAN
Wash your hands!
THE FUTURE!
PNAS 2012,in press.
Analysis of interactive bacterial cell networks
Watrous et al 2012.
Microbes maketh man (people are not only people)