A light on the horizon: New antibiotic without detectable resistance discovered in uncultured bacteria

There is a widespread concern about the increasing antibiotic resistance and the limited new drugs to treat infectious diseases, as discussed in a previous post. Consequently, the discovery of a new antibiotic active against a range of bacterial pathogens including Staphylococcus aureus has been greatly welcome, especially because no resistance to it has been found so far1.

Most antibiotics currently used in clinical practice derive from those discovered by screening cultivable soil microorganisms. However, approximately 99% of all species do not grow under laboratory conditions, this is, in a standard Petri dish. Gaining access to these microorganisms can unlock precious antibiotics unknown before. This is precisely what Kim Lewis and colleagues have done. First, they had to cultivate uncultivable microorganisms. How did they overcome the problem? By cultivating bacteria in their natural environment. From a technical point of view this means taking a sample of soil, diluting it and delivering one bacterial cell to each channel through a multichannel device. Then, the device is returned to the soil, and diffusion of nutrients and grow factors enables the grow of as much as 50% of bacteria, compared to the 1% that would grow on a nutrient Petri dish. Once a colony is formed, these bacteria can be transferred and cultivated in vitro. Placing Staphylococcus aureus on those plates allowed the identification of a β-proteobacterium, Eleftheria terrae, which produces a depsipeptide that killed the S. aureus. This antibiotic was isolated and named teixobactin. (Figure 1)

Figure 1. The structure of teixobactin and the predicted biosynthetic gene cluster. | Credit Ling et al. (2015)
Figure 1. The structure of teixobactin and the predicted biosynthetic gene cluster. | Credit Ling et al. (2015)

This compound is very powerful not only against Staphilococcus aureus but also against other Gram-positive pathogens such as Clostridium difficile and Bacillus anthracis. More importantly, is capable of killing drug resistant strains. The scientist carrying out the experiment were not able to obtain mutants of S. aureus or Mycobacterium tuberculosis resistant to teixobactin even when setting conditions that would favour it. On the other hand, teixobactin was ineffective against most Gram-negative bacteria, and luckily, had no toxicity against mammalian cells. This suggested a specific mode of action against Gram-positive bacteria, and indeed, the authors found that this molecule inhibits the synthesis of peptidoglican.

Looking deeper into the mechanism of action, the fact that no resistance had been developed against it pointed that the target is not a protein. If this was the case, mutations in the DNA would eventually lead to a modified protein that could no longer be targeted by the compound. Although many antibiotics target proteins, some are also known to bind to other biomolecules. This is precisely the case of vancomycin, which binds lipid II, the precursor of peptidoglican. The mechanism of teixobactin was shown to be more complicated, because it targets several precursors in the biosynthetic pathways for each of two major components of the bacterial cell wall, peptidoglycan and teichoic acid. Therefore, formation of a functional cell envelope is prevented, which contributes to efficient lysis, due to digestion of the cell wall by liberated autolysins. (Figure 2) The described mechanism applies to Gram-positive bacteria, which just have a peptidoglican wall around their membrane. It also explains its inactivity against Gram-negative bacteria, which have an outer membrane around the peptidoglican layer. The most interesting feature of the mode of action is that is not likeable that a resistance mechanism in form of an antibiotic modifying enzyme would emerge. It took 30 years for vancomycin resistance to appear and it would probably take longer for teixobactin.

Figure 2. A model of teixobactin targeting and resistance. The teixobactin producer is a Gram-negative bacterium, protected from this compound by exporting it outside of its outer membrane (upper panel). It targets Gram-positive organisms lacking an outer membrane, where teixobactin binds precursors of peptidoglycan (PG) and wall teichoic acid (WTA). CM, cytoplasmic membrane; CW, cell wall; OM, outer membrane; T, teixobactin. | Credit Ling et al. (2015)
Figure 2. A model of teixobactin targeting and resistance. The teixobactin producer is a Gram-negative bacterium, protected from this compound by exporting it outside of its outer membrane (upper panel). It targets Gram-positive organisms lacking an outer membrane, where teixobactin binds precursors of peptidoglycan (PG) and wall teichoic acid (WTA). CM, cytoplasmic membrane; CW, cell wall; OM, outer membrane; T, teixobactin. | Credit Ling et al. (2015)

It would be highly desirable to profit from this interesting mechanism of action and use teixobactin as a therapeutic agent. In order to assess this possibility, in vivo efficacy was tested, with promising results: it retained its potency in presence of serum, was stable and had low toxicity. Further experiments were designed to test its efficacy in a septicemia model. For that purpose, mice were infected intraperitoneally with methicillin-resistant S.aureus(MRSA) at a dose that leads to 90% of death. After one hour, different teixobactin doses were administered. With doses higher than 0.5mg per kg all mice survived (Figure 3). Moreover, the dose at which half of the animals survive was determined to be 0.2mg per kg, much lover than 2.75mg per kg of vancomycin, the main antibiotic used in hospitals to treat MRSA.

Figure 3. Single dose treatment (i.v., 1 h post-infection, 6 mice per group) with teixobactin and vancomycin in septicemia model using MRSA. Survival is depicted 48 h after infection *P,0.05, ***P,0.001. | Credit Ling et al. (2015)
Figure 3. Single dose treatment (i.v., 1 h post-infection, 6 mice per group) with teixobactin and vancomycin in septicemia model using MRSA. Survival is depicted 48 h after infection *P,0.05, ***P,0.001. | Credit Ling et al. (2015)

The discovery of this new antibiotic is truly good news. Teixobactin itself shows very promising results, but more importantly is the message that it brings: there are more antibiotics and other compounds with interesting biological activities waiting to be discovered in uncultured bacteria.

References

  1. Ling L.L., Schneider T., Peoples A.J., Spoering A.L., Engels I., Conlon B.P., Mueller A., Schäberle T.F., Hughes D.E. & Epstein S. & (2015). A new antibiotic kills pathogens without detectable resistance., Nature, PMID: http://www.ncbi.nlm.nih.gov/pubmed/25561178

Leave a reply

Your email is never shared. Required fields are marked.

Required
Required
Required

You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <s> <strike> <strong>