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Nobel prize awarded for natural product-based drug discovery,

Discovery of new class of antibiotic through innovative natural product library screen,

No decrease in rate of discovery of new natural product scaffolds between 1990 and 2015

 

Natural product libraries for drug discovery

 

Discovery of new class of antibiotic through innovative natural product library screen

A novel approach to natural product screening has enabled the discovery of an entirely new type of antibiotic [1].

To date, the majority of antibiotics have been discovered by screening the secreted products of soil microbes. However, 99% of soil micro-organisms do not grow when cultivated in the lab under standard conditions.

Now, researchers led by Dr Kim Lewis in the Department of Biology, at Northeastern University, Massachusetts, have turned to a novel approach to cultivate a greater fraction of these so-called “uncultivable” bacteria. Their approach is based on the recent finding that most soil microbes depend on metabolites secreted by their neighbours for growth [2].

To enable this, the group cultured individual soil microbes within many thousands of tiny microwells, separated from their surroundings by a permeable membrane which allowed small molecules but not bacteria to cross. This cassette was then buried in the same type of soil from which the microbes were isolated, in order to perfuse the chambers with the unique mixture of compounds derived from their soil microbe neighbours necessary for their growth. After several weeks of culture in this conducive environment, pure colonies of thousands of previously uncultivable organisms were obtained.

A screen of crude extracts of the secreted products of these new colonies revealed that many displayed antimicrobial activity against Staphylococcus aureus - a clinically relevant microbe which is commonly associated with serious hospital acquired infections and resistance to multiple antibiotics.

Activity-guided separation, using C18 high performance liquid chromatography (HPLC), was then used to isolate an active compound of 1,242 Daltons which was not reported in natural product databases. Nuclear magnetic resonance (NMR) was then used to establish the structure of the compound, revealing it to be a unusual depsipeptide containing enduracididine, methylphenylalanine, and four D-amino acids.

The new compound, called Teixobactin, displayed antimicrobial activity against a wide range of clinically relevant bacteria, and the mode of action was found to involve the inhibition of cell wall synthesis by binding to highly conserved motifs of two critical components of the Gram-positive bacterial cell wall: peptidoglycan and teichoic acid. Remarkably, cultivation of Teixobactin in a model of bacterial evolution revealed no emergence of antibiotic resistance over multiple generations, suggesting that the targets are relatively resistant to the emergence of escape mutants [1].

The discovery is particularly timely, as the incidence of antibiotic resistant infections in hospitals around the world is increasing rapidly, and some strains are resistant to all front-line antibiotics. The WHO has called for greatly expanded research efforts on the discovery of new antibiotics, in order to avert large increases in deaths due to untreatable infections [3].

The implications of the study for natural product screening are also profound. Cultivating the 99% of previously uncultivated microbes in soil alone has the potential to markedly increase the diversity of the known natural product chemical space. The new biological space has potential to reduce rates of re-discovery of compounds of the same or similar scaffolds to existing compounds, and increases potential for identification of compounds with activity against many diverse targets, including those of non-bacterial origin.

[1] Ling LL, et al. A new antibiotic kills pathogens without detectable resistance. Nature 517:455-459 (2015)
http://www.nature.com/nature/journal/v517/n7535/full/nature14098.html

[2] Nichols D, et al. Use of ichip for high-throughput in situ cultivation of ‘uncultivable’ microbial species. Appl Environ Microbiol 76:2445-2450 (2010)
http://aem.asm.org/content/76/8/2445.full

[3] WHO Global Action Plan on Antimicrobial Resistance.
http://www.who.int/antimicrobial-resistance/en/

 

Natural product libraries for drug discovery

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