biomolbioandco

Science, discussed.

An ‘invincible’ antibiotic that is bound to be defeated

The following paper was published as recently as yesterday, but already caused a bit of a stir on social media. Let’s see why.

A new antibiotic kills pathogens without detectable resistance
Losee L. Ling et al.
http://dx.doi.org/10.1038/nature14098
Nature

nature14098-f1

The isolation and characterisation of the gram-positive antibiotic teixobactin performed by the authors has been conducted with the highest standards, and uses complementary methods to provide strong evidence for their claims. Personally, I’ve found the combination of next generation sequencing and metabolic complementation analysis particularly enjoyable and a good reminder that more than ‘new’ vs ‘old’ techniques, it’s only a matter of which are the most relevant ones for any given biological question.

The reported potency and MIC values for the antibiotic suggest teixobactin could play an important role in fighting bacterial virulence, e.g. for MRSA. Bacterial growth is inhibited (by inducing cell lysis) both in pure suspensions and in animal models, significantly increasing survival rates. The proposed mechanism of action indicates peptidoglycan biosynthesis is the target, and that teixobactin most likely acts by masking/mimicking lipid substrates, not by inhibiting any biosynthetic enzyme. This mechanism explains the broad spectrum of teixobactin and its efficiency.

The generality of its action mechanism made the authors argue that teixobactin is very unlikely to generate resistance: no one enzyme can be mutated (as teixobactin does not act on one), its target is an essential component in gram-positive bacteria (and major biosynthetic changes would be required to replace it), not even the host as a defence mechanisms (besides passively inhibiting diffusion inside the cell, being a gram-negative). And this is where the controversy lies. Even though the authors carefully mention ‘no detectable resistance’ in the title, and mention the potential of gene transfer in the discussion, assuming that nature (and bacteria in particular) will not find a way around a new antibiotic goes against everything we know. The ‘long evolution’ experiment the authors perform on S. aureus (27 days) is dwarfed by the tens-of-thousands the likes of Richard Lenski, David Liu and others got us used to. In these reports, it is shown that even core metabolic processes (as growth on citrate) can be brought about if enough time to cope with a new selective pressure is given to a large enough population.

Although the efficacy and elegance of teixobactin is out of question, and this paper is a beautiful example of how top class research is performed, part of it read as if there could be an ‘ultimate compound’ in biology that evolution cannot deal with. However, it is not difficult to imagine scenarios in which internalisation could be inhibited (by permeability changes or efflux pumps), binding to its target prevented (e.g. by the action of a trimming enzyme so common in NRPS pathways) or teixobactin sequestered entirely (by a protein/metabolite with higher affinity that its target), to mention a few.

In conclusion, I believe the ‘ultimate weapon’ is not the most relevant point this paper makes, but is the one that will be criticised the most.

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About Pietro Gatti

Interested in discussing (good) Science Lover of coffee & good films. Ideas all & only my own.

2 comments on “An ‘invincible’ antibiotic that is bound to be defeated

  1. bckirkup
    08/01/2015

    They did not do the relevant experiments. They did a serial passage experiment under exposure to low concentrations; the notion is to allow walking up the fitness landscape from low to high resistance via successive mutations. However, the relevant challenges give gram positive organisms the opportunity to acquire new genes from their environment; while the environment is being enriched with antibiotic resistances of many kinds, phage are busy ferrying them around, and very large combinatorial experiments are being carried out in the gut, in wastewater, and so on.

    http://isites.harvard.edu/fs/docs/icb.topic635451.files/September%2011/Sommer_2009.pdf
    http://www.ncbi.nlm.nih.gov/pubmed/23748443
    http://www.sciencemag.org/content/347/6217/63.abstract

    Rather than simply be critical, I would like to propose that instead of the serial passage experiment, perhaps they could have recapitulated the Sommer et al experiment. Maybe others have a better idea.

  2. Brandon Findlay
    08/01/2015

    Trying to create a resistance-free antibiotic is effectively impossible. A few years back Wright and colleagues showed that random communities of bacteria (from sealed caves and permafrost) as a group had low-frequency isolates resistant to every tested antibiotic, including the synthetic ones that didn’t exist when the bacteria were last exposed to the outside world. (one cite) There’s no reason to assume this compound will fare differently.

    Teixobactin basically looks like vancomycin. Strong, uncommon resistance mechanism, doomed to eventually become useless after prolonged high use.

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