Teixobactin

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The development of new antibiotics has been a difficult task further complicated by the the rapid evolution of resistant bacteria. Teixobactin is a newly discovered antibiotic that is effective against gram positive bacteria including antibiotic-resistant strains, such as methicilin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE), without evidence of resistance development.¹ The antibiotic, isolated from the soil using a device called the iChip, works by inhibiting cell wall synthesis.¹

Introduction

An infographic on teixobactin's discovery, mechanism of action, and limitations. By Andy Brunning of Compound Interest[1]

Microorganisms have been our primary source of new antibiotics since the drugs' introduction in the 1940s.¹ However, only about 1% of all bacterial species are readily culturable in laboratory conditions.¹ NovoBiotic Pharmaceuticals in collaboration with the University of Bonn and Northeastern University reported in Nature the discovery of a new antibiotic, teixobactin, with properties that minimize the development of bacterial resistance.³ Ling et al. found teixobactin to be effective against gram positive bacteria, including drug-resistant strains such as MRSA and VRE. This antibiotic, isolated using a device called the iChip, works through inhibiting cell wall synthesis by binding to two lipid cell wall precursors. ¹

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Identification

Teixobactin was isolated from a new species, Eleftheria terrae, from soil using a high-throughput device called the iChip.¹The iChip, a collection of plates with hundreds of wells covered by two layers of semi-permeable membranes, is used to isolate previously unculturable bacteria by growing microbes in situ, in this case in the soil, where their typical environmental factors are used to cultivate the bacteria in hundreds of miniature diffusible chambers on the iChip.² Researchers diluted soil so that on average one bacteria cell is grown in each of the various one millimeter holes on the iChip plate covered by two diffusible membranes where soil Compared to standard Petri dishes, the colony count for soil bacteria using the iChip was 5 times higher when cultivating from a single colony's worth of bacteria.² Extracts from thousands of isolates were tested for antibiotic activity, and the discovery of teixobactin's properties lead to the identification and classification of E. terrae using 16S rRNA gene sequencing.¹ Relatives of E. terrae were not previously known to produce antibiotics.¹ Though the use of the iChip's cultivating abilities, other antibiotics like teixobactin could be discovered.

Mechanism of Action, In Vivo Efficacy, and Resistance of Teixobactin

A comparison of Teixobactin's activity against gram negative and gram positive bacteria using the MIC data determined by Ling et al via broth microdilution.¹ Teixobactin was extremely effective against gram positive bacteria, but not gram negative bacteria where the outer membrane prevents the drug from binding to lipid precursors in the cell wall layer.⁴ Image created by Lisette Espinosa.

Minimum inhibitory concentrations (MIC) were used to measure the effectiveness of teixobactin against pathogenic bacteria.¹ While teixobactin was not effective against gram-negative bacteria, less than 0.6 μg/mL of the drug was necessary to visibly inhibit the growth of many gram positive bacteria tested including pathogenic MRSA, VRE, Bacillus anthracis, and Clostridium difficile.¹ No toxicity toward mammalian cells was found as expected from the mechanism of action. The antibiotic works through inhibiting cell wall synthesis by binding to two cell wall precursors, lipid II and lipid III. ¹ Though researchers looked for possible teixobactin-resistant mutants using S. aureau and M. tuberculosis through plating the bacteria in media with four times their respective MICs, no resistant mutants were found.¹ Studies done in the past on vancomycin, another antibiotic that binds to lipid cell wall precursors, suggest that teixobactin's lack of development of resistance may be due to the fact that the lipids are made from organic precursors rather than synthesized de novo from DNA like proteins, making development of resistance through mutation alone more difficult.⁴ In addition, the binding target of the drug is highly conserved among bacteria.¹ Resistance to vancomycin was identified almost 40 years after the drug's discovery when it is believed that the self-resistance vector from vanomycin-producing bacteria was captured by pathogenic bacteria through horizontal gene transfer.⁴

Limitations of Teixobactin

Although resistance to teixobactin was difficult to manufacture in lab, resistance could eventually emerge in the same manner vancomycin resistance emerged, through horizontal gene transfer.¹ However, as E. terrae is gram negative and does not need carry genes for self-resistance like vancomycin-producing bacteria, the genes for resistance would likely come from other soil bacteria.¹

Further Reading

[Sample link] Ebola Hemorrhagic Fever—Centers for Disease Control and Prevention, Special Pathogens Branch

References

1. Ling, L., Schneider, T., Peoples, A., Spoering, A., Engels, I., & Conlon, B. et al. (2015). A new antibiotic kills pathogens without detectable resistance. Nature, 517(7535), 455-459. doi:10.1038/nature14098

2. Nichols, D., Cahoon, N., Trakhtenberg, E., Pham, L., Mehta, A., & Belanger, A. et al. (2010). Use of Ichip for High-Throughput In Situ Cultivation of "Uncultivable" Microbial Species. Applied And Environmental Microbiology, 76(8), 2445-2450. doi:10.1128/aem.01754-09

3. Lewis, Kim (7 January 2015). NovoBiotic reports the discovery of teixobactin, a new antibiotic without detectable resistance. Cambridge, Massachusetts: NovoBiotic Pharmaceuticals. Retrieved 7 January 2015

4. Wright, G. (2015). Antibiotics: An irresistible newcomer. Nature, 517(7535), 442-444. doi:10.1038/nature14193

5. Halford, B. (2015). Novel Bacteria-Fighter Unearthed. Chemical & Engineering News. Cen.acs.org. Retrieved 24 March 2015.

Edited by Lisette Espinosa, a student of Nora Sullivan in BIOL168L (Microbiology) in The Keck Science Department of the Claremont Colleges Spring 2014.