Jun
27
2020

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. The discovery of teixobactin took place in 2015. It is a peptide with 11 amino acid units. Teixobactin is derived from a gram-negative bacterium, Eleftheria terrae. It is the first of a new class of antibiotics that can kill superbugs. Two examples, for instance are methicillin-resistant Staphylococcus aureus and resistant Mycobacterium tuberculosis. Researchers have been battling with difficult solubility of teixobactin and problems synthesizing this peptide in the laboratory. Teixobactin binds to the membranes of the bacteria it fights. This is a new mechanism for this new class of antibiotics, different from conventional antibiotics.

Mechanisms of fighting bacteria resistant to conventional antibiotics

But it is exactly this quality that is necessary to fight the antibiotic-resistant bacteria. The researchers showed that teixobactin binds weakly to a component of the bacterial cell wall, called “Lipid II”. But they found a second mechanism, namely blocking precursors of cell membrane synthesis in the bacteria they fight. Because of these unique mechanisms it is possible for them to fight a multitude of bacteria resistant to conventional antibiotics. Teixobactin has a unique molecular structure, which makes it difficult for resistant bacteria to develop resistance to it.

Antibiotic resistance

Resistance to antibiotics is a worldwide problem. There are several factors that worked together to make antibiotic resistance such a big issue. For instance, in the past many doctors prescribed antibiotics for any viral cold, even knowing that antibiotics only work against bacteria. Aside from this, the agricultural practice of using antibiotics as a growth stimulator is also an important factor for antibiotic resistance to develop. It is the bacteria that become resistant, not the human body. Several clinical entities involving resistant bacteria exist that show the magnitude of the problem.

Flesh-eating disease

Necrotizing fasciitis (or flesh-eating disease) can develop when you swim in contaminated waters and the bacterium, Vibrio vulnificus enters through skin sores or wounds. The CDC warns that you should stay out of salt water or brackish water, if you have a skin wound. The flesh-eating bacteria, Vibrio vulnificus can become very aggressive, once it has entered the body. Right now, 1 out of 5 people who get infected will die and many people require ICU treatment. Others need limb amputations. All of this can happen within only 1 or 2 days of becoming ill. The hope is that with the development of teixobactin as an injectable medication or as an oral pill there will no longer be deaths, amputations and scarring due to this bacterium, as the antibiotic will very quickly eradicate Vibrio vulnificus. I have previously written about what hospitals can do to fight superbugs.

The most common antibiotic-resistant bacteria

Here is a brief review of the most common antibiotic-resistant bacteria.

Mycobacterium tuberculosis

Since the 1950’s and 1960’s tuberculosis was treatable with a combination of two antibiotics over a period of six months to two years. But in the last 10 years more and more resistant strains of tuberculosis have developed. This is called multi-drug-resistant TB. In 2013 statistics showed that 3.7% of newly diagnosed tuberculosis cases were multi-drug-resistant TB. Many of these cases can be traced back to prisons and homeless shelters.

Methicillin-resistant Staphylococcus aureus (MRSA)

MRSA has become a common resistant bacterium that can present with difficult to treat boils in the skin, but also as a fulminant infection as necrotizing fasciitis (or “flesh-eating disease”). About 1/3 of the cases of flesh-eating disease are caused by MRSA.

Clostridium difficile (C. difficile)

This gut bacterium is naturally resistant to many antibiotics. The rest of the gut bacteria usually suppress the growth of C. difficile. But many patients can get overgrowth of C. difficile in their gut following treatment with antibiotics. Recolonization with probiotics can help to reintroduce a balanced bowel flora. In the US about 500,000 individuals come down every year with diarrhea due to C. difficile. This leads to approximately 15,000 deaths yearly.

Vancomycin-resistant Enterococci (VRE)

Physicians find enterococci in the gut and the female genital tract of patients. They can become resistant when the patient is treated with vancomycin for another infection. The VRE can then become a problem of its own with difficult to treat infections in the genital tract of females, the gut or in wounds from surgery. It has become a problem in immunocompromised patients.

The gonorrhea causing bacteria

In the last 70 to 80 years Neisseria gonorrhoea, the cause of gonorrhea, has been treated with only one antibiotic, but gradually the bacterium developed antibiotic-resistance. Lately, with more and more resistant strains of Neisseria gonorrhoea, the CDC has recommended to treat gonorrhea with two overlapping antibiotics.

Carbapenem-resistant Enterobacteriaceae (CRE)

There are two problem bugs among this category of enterobacteria, Klebsiella species and Escherichia coli (E. coli). These bacteria reside in hospitals where they can accumulate and are present in patients with immune system compromise. Medical devices like catheters and ventilators transmit these bacteria. Once a patient is sick with CRE, there is a danger of blood poisoning (septicemia), which has a high death rate.

How do regular antibiotics kill bacteria and how can they become resistant?

Normally, when antibiotics are not resistant, they interfere with the cell membrane production of the bacteria. Specifically, conventional antibiotics prevent bacteria from synthesizing a molecule, called peptidoglycan. Without peptidoglycan bacteria are not stable enough to survive in humans. But there are other mechanisms as explained in this link how antibiotics manage to kill bacteria.

Now I like to address the question how bacteria can become resistant to conventional antibiotics. This happens with overuse of antibiotics, i.e. prescribing antibiotics when a person suffers from a viral illness where antibiotics do not work. Other overuse comes from agriculture where cattle in feed lots get antibiotics as growth promoters. The FDA is strongly criticizing this practice, because residuals of antibiotics in beef can alter the bowel flora in man. The antibiotics kill all the sensitive bacteria. But the resistant bacteria, that have undergone mutations and adapted to the antibiotics, will survive.

Why teixobactin and analogues can avoid resistance

Since the detection of teixobactin many analogues have been synthesized. A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. The teixobactin analogues need more fine tuning, but they will be a breakthrough in the treatment of resistant bacteria. As this peptide attacks two targets on bacteria, it is not easy for bacteria to develop resistance against these new antibiotics.

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

A New Antibiotic, Teixobactin Can Overcome Antibiotic-Resistant Superbugs

Conclusion

Resistant bacteria have become a serious health concern in the last decade. Physicians overprescribing antibiotics and farmers feeding antibiotics to cattle in feedlots as growth promoters were the driving forces. In 2015 came the breakthrough and discovery of teixobactin. This is a peptide with 11 amino acid units. Teixobactin is a derivative of a gram-negative bacterium, Eleftheria terrae. A new antibiotic, teixobactin can overcome antibiotic-resistant superbugs. In the meantime, researchers have been able to improve solubility by developing teixobactin analogues. More research is necessary. But all of the researchers who work in this field claim that this will very soon be extremely useful for patients with super bugs. This super-antibiotic will be a weapon fighting super bugs. Before the release of this medication clinical trials will be the next step.

Apr
07
2018

Antibiotic Resistant Bacteria Killed By Teixobactin

Antibiotic resistant bacteria killed by teixobactin would be a dream for infection specialists. In the last few decades drug resistance among antibiotics has become a major problem in chronic care homes and hospitals. Fortunately in January 2018 a publication announced that a research team from Lincoln, Great Britain was successful in synthesizing a new antibiotic, called teixobactin.

Origin of teixobactin

First of all, teixobactin is a peptide, and it comes from a soil bacterium that was difficult to culture. But a new culture method made it possible to isolate teixobactin. Subsequently the biochemists were able to create the identical antibiotic synthetically.

This moment likely is as important as the original discovery of penicillin. Experiments in the Petri dish and in mice show that teixobactin is a broad spectrum antibiotic, has no toxicity and treats all of the problem bugs that are associated with drug resistance. To the clinician it is a dream come true. For decades they hoped for an effective treatment for drug resistant bacteria. And now this seems to materialize. In the US there are 2 million drug resistant infections every year. More than 23,000 patients die from them every year.

Six problem bugs that are drug resistant

There are currently 6 problem bugs that have developed resistance. 1 in 4 nursing home patients may have one of these resistant bugs: carbapenem-resistant Enterobacteriaceae, methicillin-resistant Staphylococcus aureus (MRSA), ESBL-producing Enterobacteriaceae, vancomycin-resistant Enterococcus (VRE), multidrug-resistant Pseudomonas aeruginosa and multidrug-resistant Acinetobacter.

3 years ago a research team showed that teixobactin killed MRSA and VRE.  The underlying publication by Ishwar Singh and colleagues described how cyclic peptides their research team has successfully synthesized teixobactin analogues. He said that these findings may “lead to the first new class of antibiotic drug in 30 years”.

Mouse experiments using teixobactin analogues

The next level of evidence came from mouse experiments. Ten analogues of teixobactin were tested on mice that had infections due to drug resistant bacteria.

One team working at the Singapore Eye Research Institute could show that mice that had Staphylococcus aureus keratitis (infection of the cornea with bacteria) achieved a cure of this infection with synthetic teixobactin. An additional observation was that the amount of swelling (edema) and inflammation that is part of the infection was quickly resolving with teixobactin. This additional anti-inflammatory effect of teixobactin is an asset that will be a necessity, when it comes to treating infections in patients.

At this point there have been no clinical trials. This is the next step before physicians can prescribe teixobactin for their patients. Dr. Singh said, “We are probably around six to ten years away from a drug that doctors can prescribe to patients”.

New antibiotic treats

antibiotic resistant tuberculosis

In addition to teixobactin there is another story that gives hope for cases of resistant tuberculosis. In an Iranian publication from August 2017 it is described how compounds from the Persian shallot have full antibiotic activity against known drug resistant E.coli strains.

The same antibiotic derived from Persian shallot is also effective against resistant tuberculosis. Dr. Sanjib Bhakta and Professor Gibbons from Great Britain said that their ability to synthesize the effective antibiotics is a great breakthrough. Prof. Gibbons said: “Natural products from plants and microbes have enormous potential as a source of new antibiotics. Nature is an amazingly creative chemist, and it is likely that plants such as the Persian shallot produce these chemicals as a defence against microbes in their environment. Dr. Bhakta and I will be dedicating our research to discovering new antibiotics and understanding how they function.”

Persian shallot-derived antibiotics

Dr. Bhakta tested the Persian shallot-derived antibiotics against various drug-resistant bacteria. There were inhibitory effects on Escherichia coli, Klebsiella pneumoniae, multidrug resistant Staphylococcus aureus and Proteus mirabilis. But the most impressive inhibition (inhibiting growth by 99.9%) was against the tuberculosis bacterium, Mycobacterium tuberculosis. Consequently this is a significant finding as drug-resistant tuberculosis strains have been on the rise killing a lot of people.

Antibiotic Resistant Bacteria Killed By Teixobactin

Antibiotic Resistant Bacteria Killed By Teixobactin

Conclusion

Research has opened a door to a new era that will be ready for prime time in 6 to 8 years. Research has identified two groups of new antibiotics, synthetic teixobactins and Persian onion-derived antibiotics. They are both effective in preliminary in vitro and in vivo mouse experiments against drug-resistant bacteria. The most important effects are against Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus (VRE) and antibiotic resistant tuberculosis (Mycobacterium tuberculosis). At this stage there is an urgent need to conduct clinical trials to get FDA approval for these new antibiotics. With this approval the new antibiotics are ready for use in clinical medicine against drug-resistant infections. In the antibiotic field no such finding of that significance has occurred in the last 30 years. In the US more than 23,000 patients die from them every year. It is high time that there is a cure for these infections.