Discovery of a New Class of Antibiotic in Natural Soils;.

Multidrug resistant pathogens is a major public health concern, but the rate of antibiotic discovery has been in steady decline. Major pharmaceutical companies appear to have abandoned the effort due to a perceived low return on investment. The search for new antibiotics from microbial sources presents a difficult problem. The probability of discovering a novel antibiotic from traditionally cultivable microorganisms is estimated to be 10^-7, making such discovery seemingly impractical. This pool of microbial species, traditionally from soils, appears to be overmined. Metagenomics and combinatorial chemistry represent promising alternatives to cultivation of new species, but these approaches have yet to produce a substantial antimicrobial pipeline. Synthetic approaches were unable to replace natural products and all the newly introduced antibiotics, such as e.g. daptomycin and linezolid, resulted from revival of initially discarded compounds discovered decades ago.

The uncultivated microorganisms represent >99% of microbial diversity in nature. This unexplored, and previously unavailable, biodiversity is arguably the single most promising resource for novel antibiotics, at least for now. To explore this resource, we designed and tested several novel cultivation methods sharing one basic idea: natural environment contains all the growth factors necessary for microbial growth, and so such environment could be used as the source of such factors. In one of the new devices, termed “isolation chip”, or ichip for short, individual microbial cells from soil are placed into an array of miniature diffusion chambers, which are then incubated in contact with the soil sample.  We achieved microbial recovery orders of magnitude higher than in parallel experiments employing conventional cultivation. We also observed a significantly higher novelty of isolates grown in ichips. Ichip industrial application resulted in identification of several novel antimicrobials. One of them, teixobactin, represents a novel class of antibiotics and kills gram-positive bacteria with no detectable resistance.