It’s not often that I feature a mighty Nature paper on this ‘lil old blog, but this is a big one. A team from Northeastern University in Boston and a small company called NovoBiotic Pharmaceuticals have discovered a truly novel antibiotic, called ‘teixobactin’.
The finding stems from the fact that 99% of microbes in the external environment cannot be cultured in the laboratory. In order to overcome this problem, the authors ingeniously brought the laboratory to the soil by using the iChip (pictured below). The iChip is a way of capturing the growth of a microbe in its natural environment. Curiously, once grown in the iChip, most of the colonies could then be sub-cultured in the laboratory. When using the iChip, around 50% of the microbes in the soil can be cultured (compared with 1% using conventional methods).
The authors then screened extracts from an awful lot of isolates (10,000) for antimicrobial activity, and found one that stood out: ‘teixobactin’. It’s a novel cell wall inhibitor that interrupts peptidoglycan synthesis not by targeting proteins (such as the enzymes targeted by β-lactams), but by targeting lipids.
Teixobactin has impressive activity against a range of Gram-positive pathogens of importance to healthcare including S. aureus, E. faecium / faecalis, various streptococci, M. tuberculosis and, importantly, C. difficile. The authors found that teixobactin had equivalent activity to oxacillin (methicillin) in vitro, and superior activity to vancomycin both in vitro and in an animal model.
However, there are some problems:
- Firstly, and most importantly, there is no activity against Gram-negative bacteria. Since the source microbe, the newly described Elftheria terrae, is a Gram-negative bacterium, this is no surprise, otherwise it would inhibit itself in the soil!
- Secondly, the antibiotic is still a long way from the clinic, and has to undergo a series of rigorous human clinical trials before reaching the pharmacy shelves.
- Thirdly, the authors made the promising discovery that they did not identify reduced susceptibility to teixobactin despite serial passage to sub-inhibitory doses for 27 days. The press have had a field day with this, and are talking in terms of “resistance resistant” antibiotics. But this is too much: the authors parallel the potential for resistance to teixobactin with the potential for resistance to vancomycin – and we are increasingly seeing clinically meaningful reduced susceptibility to vancomycin. There’s a rather obscure and quite frightening study showing that vancomycin resistance could be just around the corner: the study found that S. aureus exposed to sub-lethal doses of chlorhexidine as a surface biofilm became resistant to vancomycin after 48 hours (MIC >128 mg/L). So, bacteria will become resistant to whatever we throw at them, to a lesser or greater degree, given time and sub-lethal exposure.
So, teixobactin represents and exciting and huge leap forward in the process of antibiotic drug discovery – and we can expect more novel antibiotics to follow. However, we’d be foolish to think that resistance to teixobactin will not emerge in time.
Image: NBC news.
Reflections on Infection Prevention and Control 
Personally i can’t believe how much media coverage and hyperbole this paper has generated (Nature clearly has a good Press office). While the way they discovered the new molecule, teixobactin (growth of previously non-cultivatable soil bacteria on a iChip emerged in soil) is somewhat novel and exciting, the compound itself in targeting lipid II has a similar MOA to the lipoglycopeptides (such as the recently FDA approved oritavancin) or lantibiotics such as nisin which is used as a preservative. Like teixobactin, both are cidal with low resistance potential but also Gram positive only agents so not really the answer to our global MDR problems that the press would seem to suggest.
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Jon, I couldn’t agree more! An exciting find using a novel way….but, we would all be foolish to think we have found the magic bullet. I will remain guardedly optimistic, with a healthy side of suspicion until further testing tells us differently. Thanks for the important post.
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Hi Jon
What exactly do you mean by this sentence: “S. aureus exposed sub-lethal doses of chlorhexidine as a surface biofilm became resistant to vancomycin after 48 hours (MIC >128 mg/L).” I thought antibiotics are not resistant to aniseptics. I have a pt that cleanses with chlorhexide several times a day prior to doing urinary self-catheterization. Are we predisposing him to VRSA? Love to hear your thoughts.
Best regards,
Diane
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Nice post. It’s getting national network news coverage in the US and your comments are spot on. Exciting but not the cure and its years from potentially getting to the market. I doubt “no resistance potential” TV is telling the public. This premature promotion tends to negate todays stewardship message that we are running out of effective antibiotics
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Interesting and informed comment art, and like you point out, this compound is a ways our (5-6 years if it passes muster, succeeds in trials) — it’s years behind another similar antibiotic that I haven’t seen get the attention it deserves. The one I’m talking about just finished Phase 2B trials, was granted QIDP status under the GAIN act, and has had results that match or surpass Daptomycin’s 7 day treatment either as a 3 day or as a 1 day course of treatment. Even better, testing indicates that bacterial resistance is extremely unlikely to develop. The company is Cellceutix, and one of their leading drugs in development, Brilacidin, also attacks the bacteria cell walls. Right now, it’s going into Phase 3 for severe skin infections, such as MRSA and other resistant superbugs. What to know about it: attacks bacterial cell walls, single dose treatment has proven very effective with minimal drug-related side effects, works just like host defense proteins. It’s part of a new class of antibiotics called Defensin Mimetics. Bacteria would need to evolve an entire new cell wall structure to develop immunity, similarly to Teixobactin, only this drug is a lot further along in the approval process. Also, Cellceutix has developed a room-temperature stable compound and are going to start a Phase 2 trial on Diabetic Foot Ulcers shortly. You can Google it and check out some of the company’s press releases, including published results. This research is the tip of the iceberg.
http://cellceutix.com/brilacidin/
Click to access Host_Defense_Antimicrobial_Peptides.pdf
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Also this:
Comparative Mechanistic Studies of Brilacidin, Daptomycin and the Antimicrobial Peptide LL1
Click to access AAC.02955-14.full.pdf
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Have you perchance ever looked at the (now about to begin Phase III) antibiotic Brilicidin? It is under development by a small american company Cellceutix and is supposed to be active against both gram + and – bacteria. It was tested first for absissi, head to head against Daptomycin and was statistically equivalent to Daptomycin with just a one-day intravenous administration, vs. the seven-day Daptomycin.
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Jon, I would be very interested in reading your evaluation of Cellceutix new defensin mimetic based antibiotic platform. The first one (Brilacidin) just finished an FDA Phase 2b study on ABSSSI (including MRSA) using a single dose protocol. This one time dose of Brilacidin compared favorably to 7 day dosing with Daptomycin. Defensin Mimetics are also said to be “resistance resistant”. I would appreciate hearing your opinion of that assessment. Thanks.
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Thank you for applying balance to the “news” machine that thrives on scandal and innuendo. We end up trying to translate the science of cleaning and disinfection to custodians, housekeepers and managers of facilities.
Reliance on your expertise and clear factual information makes it so easy to help others keep their balance as well.
Penecillin was the original Silver Bullet and we know what happened with that one and how fast.
Good soil and particulate removal followed by topical and specific focussed disinfectants is what we teach. Great procedures not just super products seems to work on a daily basis. Thanks again for the insight into the challenging world of pathogens and our relationship to them.
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Hi Jon, thanks for throwing light on several questions which came in the mind after reading so much stuff about teixobactin !! In India Gram positives are seldom a problem. The incidence of MRSA and VRE is probably less than 2 %. In my ID practice, I must be writing one or two prescriptions of Daptomycin per year. At the same time , I am writing 3-4 carbapenem prescriptions per day!!! Our Esbls and MDR GNBs are huge problem. Waiting for the day when we will find something for these bugs.
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MDR-type resistance will always be a problem. For example, that’s a way that survivors of chlorhexidine can resist vancomycin. And of course this novel peptide structure might require modification to be successful in the clinic. But it’s nice that someone is looking for new antibiotics. And their method for screening is pretty clever.
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Nice discussion and many good points. Something that struck me about the study is that besides discovering an interesting novel natural product that has promise as a new antibiotic class, a key part of this Nature paper is the methodology used to conduct their natural products screen. They developed a really cleaver yet practical way (the iChip) to grow bacteria that are recalcitrant to culturing under routine lab conditions, and hence generally excluded from natural product screens in the past. It will be interesting to see if this new method yields other useful natural products, whether as potential antibiotics or as therapeutics for other diseases.
I also have my reservations that bacteria will never become resistant to teixobactin. My concern is that since teixobactin is a natural product, soil bacteria have already been exposed to it for an extended period of time so it is not unreasonable to expect that some strain someplace already is resistant. Perhaps the real experiment to test for the possibility of a resistance mechanism is to make use of the same iChip system to challenge a screen of bacteria obtained from the same soil samples with teixobactin.
It will be an interesting story to follow over the next few years to see if teixobactin or a derivative reaches the clinic. We certainly need new antibiotics.
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The information is very useful.
http://veterinarymicrobiology.in/teixobactin-a-new-antibiotic-kills-pathogen-without-detectable-resistance/
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