Mud gives us more antibiotics!

“A new antibiotic kills pathogens without detectable resistance” is the rather uninspiring title of what is being hailed as a landmark piece of work published by Nature this month. The work by Ling, Schneider, Peoples et al as a collaboration between pharmaceutical companies and research scientists, in Massachusetts in the USA and Bonn in Germany, presents the first new class of antibiotic to be discovered in more than 30 years. What’s more, the authors claim that resistance to this new agent is unlikely to occur. So what’s the hype all about and should we all heave a sigh of relief that the antibiotic drought is over? Perhaps that would be a bit premature…. Let’s look at Teixobactin a bit further (and what better way than in the format of the book Microbiology Nuts & Bolts?).

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Teixobactin
Teixobactin is the first in a new class of agents called lipid II binding antibiotics.

Mechanism of Action

• Bactericidal
  
• Teixobactin inhibits synthesis of peptidoglycan by binding to the first sugar moiety of the lipid II complex of peptidoglycan precursors thereby preventing cell wall formation by bacteria
• Activity is not dependent on the presence of this sugar moiety which allows Teixobactin to kill Mycobacterium tuberculosis which has a different sugar to other bacteria
  
• Teixobactin inhibits teichoic acid synthesis which releases autolysins, proteins which can then destroy the cell wall and kill the bacteria
  

Mechanisms of Resistance

• Resistance to Teixobactin has yet to be described in Gram-positive bacteria, but if it occurs it is likely to be due to the evolution of enzymes that destroy the antibiotic before it can act. This is because the antibiotic is exploiting a fundamental and highly conserved component of bacterial cell wall synthesis; the bacteria cannot survive without this mechanism and cannot change the mechanism. The target is also not a protein and therefore spontaneous mutation of the active site is unlikely to occur. This is similar to the antibiotic Vancomycin; however Vancomycin resistance does now occur...it just took 30 years to evolve
• Teixobactin is unable to penetrate the cell membrane of Gram-negative bacteria and therefore cannot reach its active site in Gram-negative bacteria. This antibiotic agent is naturally produced by the bacterium Eleftheria terrae (a Gram-negative bacterium). If Teixobactin killed Gram-negative bacteria it would kill the bacterium that produced it, so it makes sense that there is a mechanism of resistance which prevents this from happening!

Pharmacology and Pharmacodynamics

• These are yet to be described, although the preliminary animal studies show Teixobactin to be effective at treating Meticillin-resistant Staphylococcus aureus and Streptococcus pneumoniae in mice without killing or causing side-effects in the mice

Spectrum of Activity of Teixobactin

Click for larger image

Cautions and Contraindications
Too much optimism!? I don’t want to rain on everyone's parade but I think we have to see this new antibiotic for what it is. The technology that has led to the discovery is exciting (for a Microbiologist it is anyway!) but there a few potential drawbacks before this hits the shelves of a pharmacy near you.

1. This antibiotic only has Gram-positive activity, and we still have other agents for treating infections due to Gram-positive bacteria such as Vancomycin, Daptomycin, Linezolid and Tigecycline. The impending disaster where we are going to run out of antibiotics is for Gram-negative sepsis. We need new anti-Gram-negative antibiotics urgently!
   
2. It takes at least 5 years for a new drug to come to market, so we still have a long time to wait before Teixobactin is available for use in patients
3. New drugs tend to be expensive and therefore restricted by health services which have to justify the cost effectiveness of any treatments
   
4. Developing new antibiotics is expensive and less cost effective for pharmaceutical companies; therefore they are less inclined to develop antibiotics which are prescribed as short courses. Consider which is more profitable: 5 days of an antibiotic for an infection or 30 years of the latest statin for someone’s heart disease?
   
5. Sometimes unexpected side-effects occur when new drugs are trialled in humans even though they were not seen in animals. You may remember the unexpected adverse reaction to an immunomodulatory drug known as TGN1412, in London in March 2006, which resulted in all six of the first volunteers being admitted to an intensive care unit due to "unforeseen biological action in humans” and the resulting insolvency of the company producing the drug.
   

Side Effects
As Teixobactin has not yet been trialled, let alone licensed, there is no data available regarding its side effects. However the most important consequence or “side effect” of the discovery of this new class of antibiotics is in the way it was discovered.

• In the past, new antibiotics were derived from environmental microorganisms. This is why many of them end in the term mycin (e.g. Clarithromycin), which indicates they are derived from fungi, or if they are synthetically derived the antibiotic name ends in micin instead (e.g. Gentamicin). Traditionally new antibiotics were grown in laboratories simulating the environmental conditions of the fungi or bacteria but there was only a success rate of approximately 1%. No wonder there have been no new antibiotics! 
• Ling, Schneider, Peoples et al have developed a new technique which allows them to grow up to 50% of soil bacteria. They do this by dipping a metal slide with multiple microscopic holes into molten agar containing bacteria. When removed the tiny holes fill with plugs of agar. They have called the inoculated slide an iChip. The iChip is then covered in semi-permeable membrane and put back in to soil. Mother Nature is far better at culturing bacteria than us laboratory staff! The semi-permeable membrane allows nutrients to feed the bacteria on the iChip without the bacteria being attacked or overgrown by other soil organisms. This is such a simple concept but a very clever solution to provide the bacteria with the perfect conditions for them to grow. Once the bacteria are growing well they can be moved into the normal laboratory environment, the numbers multiplied and then applied to plates containing troublesome bacteria e.g. MRSA to see if these new bacteria produce chemicals which will kill off the competition (the MRSA). If they do, these are exciting new antibiotic properties and researchers then concentrate on finding the specifically active chemicals and developing new drugs
• In the case of Teixobactin, it was the new bacterium Eleftheria terrae which grew on the iChip. Eleftheria terrae was then cultured on agar plates with Staphylococcus aureus and the colonies of Eleftheria terrae inhibited the growth of the Staphylococci. This last bit of the experiment is reminiscent of the observation by Alexander Fleming, who saw that the fungus Penicillium notatum inhibited the growth of Staphylococci, leading to the discovery of the penicillin antibiotics.

• The really exciting bit is that the technique used to discover Teixobactin can be applied to screen many other bacteria for possible antibiotic compounds, potentially leading to many new antibiotic agents. Most significant for the clinically setting would be the discovery of new antibiotic agents with anti-Gram-negative properties.

Monitoring

• The media, Chief Medical Officer, medical publications and many Microbiologists may be excited about this new antibiotic, it is the first in 30 years; however in my opinion Teixobactin is unlikely to be the most clinically useful antibiotic as current antibiotics cover the same spectrum of bacteria.  The ground breaking and most exciting part of the discovery by Ling, Schneider, Peoples et al is the technique they have developed for screening environmental bacteria for new antibiotics. That is very exciting for us Microbiologists!
• We will watch this space eagerly…