New Antibiotics: Soil bacteria show the way

The need for new antibiotics is a hot topic at the moment – the Longtiude Prize 2014 has offered £10 million for solving the problem of global antibiotic resistance. Since Fleming identified penicillin in 1928, antibiotics have revolutionised medicine, but bacterial resistance to antibiotics is spreading – in 2012, there were an estimated 450 000 new cases of  multidrug resistant tuberculosis in the world (World Health Organisation). A recent paper in Nature suggests that soil microbes may be a rich source of novel antibiotics.

“It is likely that additional natural compounds with …. low susceptibility to resistance are present in nature and are waiting to be discovered.” – authors of study

Historically, microbiology has been limited in its scope as only a small percentage of all microbial species are able to be cultured in laboratory conditions [See IBPMS lectures]. The authors used a new device they termed the ‘iChip’, which allowed previously uncultured bacteria to grow in a soil based environment within a 96 well plate, and then tested these bacteria for their ability to inhibit the growth of the gram-positive pathogen Staphylococcus aureus. Using this technique they identified a new species of gram-negative β-proteobacteria named Eleftheria terrae which produced an antibiotic compound the authors named teixobactin.

The methodology used to identify Teixobactin. Reproduced from Nature.
The methodology used to identify Teixobactin. Reproduced from Nature.

Teixobactin is an unusal peptide based molecule, which contains both D- and L-amino acids, as well as the non-protein amino acids enduracididine and methylphenylalanine. Teixobactin was very effective against gram-positive bacteria, including strains already resistant to multiple antibiotics (see graph), and when tested in a mouse model significantly reduced the levels of infection.

Teixobactin is an effective antibiotic against S. aureus, and is more effective than the commonly used antibiotic vancomycin. c.f.u = colony forming units. Reproduced from Nature.
Teixobactin is an effective antibiotic against S. aureus, and is more effective than the commonly used antibiotic vancomycin. c.f.u = colony forming units. Reproduced from Nature.

The reason for teixobactin’s effectiveness is that it inhibits peptidoglycan synthesis, thus weakens the bacterial cell wall. It therefore has an analogous overall mode of action to penicillin [See IABoC Living Cell Lectures], but there is no resistance to this compound. Teixobactin binds to a number of different components in the cell, none of which are proteins. This means that it may be more difficult for resistance to evolve, as there will be less direct selection pressure for the protein sequence to change. Teixobactin therefore represents a novel class of antibiotic that may have high therapeutic potential.

Reference: A new antibiotic kills pathogens without detectable resistance. Ling et al. (2015) Nature DOI:10.1038/nature14098

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