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Origins and Evolution of Bioactive Molecules(Chemical Signalling)

1A brief history of antibiotics(co-evolution of antibiotics and their resistance)?1940195019601970198019902000The Dark Ages(Semmelweis)PrimordialGoldenPharmacologicBiochemicalGenomicHTSTargetDisenchantment(Semmelweis)(again!)

PenicillinasediscoveryAntibiotic resistance plasmidsIncreasing Antibiotic ResistanceTransmissiblefluoroquinoloneresistanceFDA Office ofNew DrugsTHE LEAN YEARS***MRSA: UK*, US**Production: 50kg>106 tons 2

Side Effects of StreptomycinHeadacheNauseaHearing difficulties, deafness Ringing sensation in the earsLoss of balanceFatigueDifficulty in passing urineItchy rashes on the skinbut it cured TB!

Albert Schatz and Selman Waksman Who deserved the Prize?Fifty years of Industrial Research on AntibioticsEnvironmentalDoubling time: monthsAeration: lowNutrients: variableCarbohydrate: limitedWater: variableTemperature: 0-40pH: 2-10Yield: grams

ProductionDoubling time: hoursAeration: high*Nutrients: high and constantCarbohydrate: highWater: unlimitedTemperature: 25-30pH: 6-7Yield: grams

*Typical substrates for fermentationMolasses (blackstrap)Fish Meal (herring, anchovy)Citrus pulpAsparagus juiceCottonseed oilMalt extractBeef extract Bovine bloodPork liverDistillers solublesHydrolysed rabbit fur

SOME NUMBERSNumber of bacteriophages on Earth 1x1031Number of bioactive molecules in the Parvome>5x1030Number of microbes on Earth 5x1030Number of stars in the Universe7x1021Number of humans on Earth6x109Number of microbes in all humans6x1023Number of human cells in one human1x1013Number of microbial cells in one human gut1x1014Number of human genes in one human2.5x104Number of microbial genes in one human gut3x106Combined length of all bacteriophages on Earth108 LyDiameter of the Milky Way105 Ly* The US national debt>1x1014* Number of bubbles in one bottle of Champagne1x105(Revised from Kyrpides, 2009)

(Rumbaugh, 2007)The ParvomeInter-Kingdom Signalling7Origins and Evolution of Bioactive Small MoleculesDistribution: universal, ancientBioactivities: wide range, concentration-dependenceReceptors: mostly macromolecules (cross-species)Structures: small number of major classes (with decoration)Biosynthesis: frequently assembly lineProperties and applications: multitudinous

The Ages of Planet Earth

(bio)Chemical Evolution Hadean Period LUCA(Last Universal Common Ancestor) (Modern) Tree of Life(RNA World)RibozymesMeteorites and primordialreactions Specialised Microbial & Plant MetabolismPrimary Secondary The Tree of Life-2.0-4.0-0.1-1.0-3.0Origin of Earth (4.5 Billion years)Last common ancestor2.31.51.0ProteobacteriaCyanobacteriaPlantsDrosophilaCrenarchaeota Euryarchaeota Gram positivesMouse0.1?3.8Anoxic(H2, NH3, CO2,)Chemical evolution/Prebiotic synthesis of biomoleculesOrigin of oxygenicphotosynthesisIncreasing [O2]in atmosphereOrigin of Metazoans20% [O2] Cambrian PrecambrianAge of DinosaursOrigin of EukaryotesOrigin of Prokaryotes2.1Amitochondriate Bacteria Eukaryotes Archaea11 Aminoglycoside biosynthesis in a streptomycete

MODULAR ASSEMBLY LINESFOR BIOACTIVE COMPOUNDS

Polyketide synthaseNonribosomal peptide synthaseTetracycline, rapamycin, erythromycin Daptomycin, polymixin, vancomycin

Carbonaceous meteoritesas sources ofchemical intermediates Pizzarello & Shock (2010)

Primordial amino acid components of non-ribosomal peptides-alanine, -aminobutyric acid, -aminobutyric acid, -amino-butyric acid, -amino-isobutyric acid, ,-diaminobutyric acid, ,-diaminopropionic acid, -hydroxy--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 evolutionTranscription (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 Ribosomes30S50SThis 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

The Davies Lab, October 2011

Tantalus Mountains,BCKEEP CLEANWash your hands!

PNAS 2012,in press.THE FUTURE!

Analysis of interactive bacterial cell networksWatrous et al 2012.

Microbes maketh man (people are not only people)