Feb
06
2021

Researchers Developed a New Antibiotic to Solve Antibiotic Resistance

In Philadelphia, PA Wistar Institute researchers developed a new antibiotic to solve antibiotic resistance. In the past 10 to 15 years antibiotic resistance has caused difficulties to cure infectious diseases. But Wistar Institute researchers were able to develop a new class of antibiotics that does not only kill bacteria, but also stimulates the immune system to fight the bacteria. The WHO has published a statement in July 2020 about the topic of antibiotic resistance.

This report points out that pneumonia, tuberculosis, blood poisoning, gonorrhoea, and foodborne diseases are becoming harder to treat because of multiple antibiotic resistant bacterial strains. Sometimes physicians find it impossible to successfully treat these conditions. The Wistar Institute research hopefully will have the solution to overcoming resistance to antibiotics. An overall description of what the Wistar Institute researchers did is summarized here.

Development of antimicrobials named dual-acting immuno-antibiotics

The researchers developed a new class of antibiotics that have a dual action of being immunostimulants and antibiotics (DAIA antibiotics). This makes it much more difficult for bacteria to develop resistance. Conventional antibiotics usually target functions of the bacteria that are essential. This involves the synthesis of nucleic acid and proteins. It also targets the building up of cell membranes and metabolic pathways in the bacterium. But bacteria can fight back by becoming drug resistant and mutating the bacterial target of the antibiotic. This renders the antibiotic powerless against the bacteria that researchers originally designed to eliminate.

The researchers argued that attacking bacteria on two different fronts makes it hard for them to develop resistant strains.

Interruption of essential metabolic pathway in most bacteria

The first the researchers focused on was a metabolic pathway that is essential for most bacteria, however it is absent in humans. This makes it an ideal target when you want to develop an antibiotic. The researchers chose to block an essential pathway in the pathogenic bacteria. More about this pathway is explained in this link. Isoprenoids are lipid compounds common in membranes of bacteria and vital for their survival. There is a key enzyme that is necessary to build up isoprenoids. It has the name IspH enzyme. The Wistar researchers concentrated on finding compounds that were able to inhibit the IspH enzyme. Most compounds they found were not able to penetrate the bacterial cell wall. However, they found compounds that penetrated the bacterial wall and inhibited the IspH enzyme. The researchers tested the new antibiotics against resistant gram-positive and gram-negative bacteria. They were superior to conventional antibiotics.

Immune activation of the novel antibiotics

The Wistar Institute researchers showed that the antibiotics that inhibit the IspH enzyme are also creating powerful antigens against which the immune system mounts a strong immune response. With the dual action of being immunostimulants and antibiotics the antimicrobial agents are much more powerful than any existing conventional broad-spectrum antibiotic. The researchers tested a number of new DAIA antibiotics and could demonstrate that they were non-toxic to human cells. They also tested them against a wide range of pathogenic gram-negative and gram-positive bacteria and found that they were very potent.

Farokh Dotiwala, M.B.B.S., Ph.D., assistant professor in the Vaccine & Immunotherapy Center and coauthor of the study said: “We believe this innovative DAIA strategy may represent a potential landmark in the world’s fight against AMR, creating a synergy between the direct killing ability of antibiotics and the natural power of the immune system.” AMR stands for antimicrobial resistance.

Researchers Developed a New Antibiotic to Solve Antibiotic Resistance

Researchers Developed a New Antibiotic to Solve Antibiotic Resistance

Conclusion

The emergence of more and more resistant bacterial strains makes it difficult and expensive to treat bacterial infections. But the Wistar Institute published a research paper that introduces us to a new class of antibiotics. They have a dual action of being immunostimulants and antibiotics (DAIA antibiotics). The antibiotic action is a novel approach in that a DAIA antibiotic blocks an essential pathway in the pathogenic bacteria. This coupled with a strong immune response from the body against the bacteria ensures that no resistance against the DAIA antibiotics can develop. Studies with human cell cultures showed that the DAIA antibiotics are well tolerated. Human studies about various diseases due to antibiotic resistance will follow. This new antibiotic class has great potential to treat resistant bacteria, which will mean much better survival rates for persons with serious infections.

Sep
26
2020

A New Antibiotic Against Methicillin Resistant Staphylococcus aureus

A US study describes a new antibiotic against methicillin resistant Staphylococcus aureus. It is a lysin-based antibacterial agent.

Physicians have been looking for years for a solution regarding the increasing antibiotic resistance problem. But several attempts in the past have failed.

Staphylococcus infections are the most common bacterial infections of human skin, of soft tissue, joints, bones, and pneumonia. In addition, it can cause endocarditis (=infection of heart valves) and lead to blood poisoning (septicemia).

Staphylococcus aureus is the underlying bacterium behind staph infections. With the introduction of new antibiotics  it takes only 1 to 2 years before this bacterium learns to become resistant. Researchers noticed that the bacteria start to produce lysins and suddenly they are resistant to the latest antibiotic. Further research zeroed in on lysostaphin, which was active against resistant Staphylococcus bacterial strains.

Deimmunized lysostaphin

Lysostaphin is an antibacterial peptide described here in detail. But there still was some interference with immunologically active surface antigens that scientists were later able to overcome. Researchers succeeded lately in removing some of the surface antigens and develop deimmunized lysostaphin. This is what this publication is all about.

It describes how T cells cannot detect the surface antigen properties of deimmunized lysostaphin. This way none of the strength of deimmunized lysostaphin gets lost in the fight against resistant staphylococcus that normally form anti-drug antibodies. Researchers pointed out the importance of the deimmunization process to make deimmunized lysostaphin invisible to the T cells of the immune system.

Vigorous testing of deimmunized lysostaphin

The researchers who investigated the efficiency and safety of deimmunized lysostaphin did the following tests.

  • Although lysostaphin was deimmunized, it retained potent in vitro and in vivo anti-staphylococcal activity. In vitro studies involving Petri dishes with methicillin resistant Staphylococcus aureus showed the effectiveness of deimmunized lysostaphin. In vivo testing in a mouse and rabbit model also showed effectiveness.
  • Deimmunized lysostaphin showed reduced immunogenicity in vivo. Researchers tested this in mice and compared the results to regular lysostaphin, where there was a swift immunological response.

More points regarding deimmunized lysostaphin

  • Immune evasion allows for repeated efficient dosing of deimmunized lysostaphin. This means that the physician can administer the antibiotic (the deimmunized lysostaphin) to fight the methicillin resistant Staphylococcus aureus with several daily doses.
  • The deimmunization process allows deimmunized lysostaphin to evade the immune response that occurs to regular lysostaphin. This prevents future resistance development. It also prevents that the immune responses weaken the anti-methicillin resistant Staphylococcus aureus response.
  • Researchers showed in a difficult rabbit endocarditis model that deimmunized lysostaphin treats MRSA infection successfully. Endocarditis is an infectious disease, which is both difficult to treat in rabbits, but also in humans. For this reason, rabbits are often used as a model when new antibiotics are developed. If they are successful in the rabbit model they often get approval later for human treatments.

Deimmunized lysostaphin in humans

Unfortunately, we are still a few years away from using deimmunized lysostaphin in humans. After successful use of lysostaphin in mice and rabbits the next logical application is to launch human clinical trials. I am convinced that this will be the next step and very likely will be successful.

A New Antibiotic Against Methicillin Resistant Staphylococcus aureus

A New Antibiotic Against Methicillin Resistant Staphylococcus aureus

Conclusion

Researchers found a new antibiotic against methicillin resistant Staphylococcus aureus in a lysin-based antibacterial agent. This peptide has surface antigens that scientists had to removed to make it more effective. The end result was a deimmunized lysostaphin. Researchers tested this new antibiotic that is effective against many antibiotic resistant strains of bacteria successfully in mice and rabbits. The next step is testing in humans. This involves several phases of clinical trials. These clinical trials have to show that there is a lack of toxicity. In addition, they have to show that the new antibiotic is effective against resistant bacteria. I estimate that this process can still take about 5 years from now before the clinician can use this antibiotic routinely. As the new antibiotic is a polypeptide, it the patient cannot take it orally, as the gut is digesting it. The patient has to take it by injection.

Aug
04
2018

Phage Therapy Against Superbugs

Introduction

Phage therapy against superbugs is the latest concept in treating infections. Antibiotic resistance has developed into a huge clinical problem. Every year in the US about 2 million people have infections from antibiotic resistant bacteria, and 23,000 people die as result of it. Certainly, there is a desperate need to find alternative treatment options to treat antibiotic resistant infections. One such option is to use phages, a specific form of viruses to treat antibiotic resistant bacteria. Here is a scientific overview regarding the use of phages for the treatment of antibiotic resistant infections.

History of phages

The observation of phages attacking bacteria goes back more than 100 years. The French Canadian microbiologist, Félix Hubert d’Herelle (1873–1949) described in 1917 what bacteriophages are. He also coined the term of “phage therapy” for the treatment of bacteria with phages. Dr. d’Herelle recognized phages to be virus-like organisms that attacked bacteria and could kill them. When Fleming detected antibiotics, phage research came to a halt. Drug companies invented more and more antibiotics, as it was easier to kill bacteria this way. But now with emerging resistances of bacteria to antibiotics, there is a sudden revival of the 100-year old research on phages. The problem is that there has not been much clinical experience with phage therapy against super bugs until lately. In 1923 Dr. d’Herelle co-founded the Eliava Institute in what is now Tbilisi, Georgia. This institute has the world’s most comprehensive database on phage therapy in man.

Two clinical examples of phage therapy against super bugs

Chronic prostatitis due to superbug

Pranav Johri, a Canadian of Indian descent was suffering of a chronic prostate infection. Physicians had used five different antibiotics, but all to no avail. His doctor told him that he had a chronic prostatitis problem for which there was no cure. But Pranav saw another specialist who determined that Pranav had a prostatitis due to a superbug, which was resistant against all the common antibiotics. Pranav traveled to the Eliava Institute in Tbilisi, Georgia. He paid 6000.00 CAD and had three treatments. After the first treatment his temperature became normal for the first time in months, and his chronic pain subsided. He and his wife were so excited that they felt like celebrating. They did sightseeing, went out to restaurants and enjoyed their travels, all things he was unable to do for months. Pranav had finally received a cure with phage therapy to his chronic prostate infection.

Enteric infection due to superbug

Tom Patterson who had visited Egypt in 2015 together with his wife fell ill on the last night of his holiday. Eventually he went into a hospital in his hometown, San Diego. The doctors told him that he would likely die. He had acquired a multi-antibiotic resistant infection. He was slipping in and out of consciousness. His wife, Steffanie Strathdee, an infectious disease epidemiologist, remembered having heard about phage therapy during a virology class during her training in Toronto. Tom received two separate phage cocktails that two separate research teams in the US had prepared for his condition. He received the first dosage into his abdomen.

Intravenous phage therapy

The second administration was intravenously. There are only a handful of patients who had received treatment with phage therapy in the US; he is probably the first one who received phage therapy intravenously. A few days later he woke up. He had to relearn basic life skills like swallowing and speaking. But he made a full recovery from a serious disease with multi-antibiotic resistant bacteria. The University of California San Diego School of Medicine had helped Tom to recover from his illness. They announced at the end of June 2018 that they would be opening the Center for Innovative Phage Applications and Therapeutics in San Diego.

Modern phage technology

Basically phages are viruses that specialize in killing bacteria. They exist in nature wherever bacteria grow and help that they do not over-proliferate.  But they can be useful in fighting difficult to treat bacterial infections as well, like pseudomonas ear infections, Clostridium difficile gut infections or Methicillin-resistant Staphylococcus aureus infections in skin wounds. In the former Soviet Union and in the Eliava Institute in Tbilisi, Georgia, extensive phage research has accumulated valuable data over decades. In the West physician relied on the power of antibiotics, and phages were left on the back-burner of the research lab.

Genetic engineering of phages and toxins produced by phages

Combining phage research and genetic engineering research we are entering a new era of manufacturing biological compounds that can kill bacteria similar to antibiotics. Here is a review article of this new exciting field. I only include this link to show that researchers are now getting a handle on phages. They can be genetically modified to specifically attack one kind of bacterium. The DNA of the phage can be isolated and injected into bacteria. I do not expect you to understand all of what is discussed in this link.

Phage Therapy Against Superbugs

Phage Therapy Against Superbugs

Conclusion

As a result phages are more and more in use to treat difficult chronic infections where bacteria have become resistant to multiple antibiotics. It requires a team of experts who are familiar with phage cocktails. The cocktail is a careful combination of various phages that will fight the antibiotic resistant infection.The composition of it has to be according to the bacteria present in the patient’s bacterial flora. As shown with two clinical examples very sick patients can recover relatively quickly from their chronic infections. After this breakthrough more and more centers for phage therapy will open and this should help reduce the death rate from antibiotic-resistant infections.

Aug
01
2007

New Cure For Drug Resistant Bacteria At The Horizon

Drug resistant bacteria (like MRSA, methicillin resistant Staphylococcus aureus) have developed in many hospitals and have caused more than 2 million infections in the US alone of which 90,000 people died. Yet so far research regarding this problem has been very slow and unsuccessful. In Canada there was an outbreak of E.coli, which left 14 people severely ill and simultaneously there was a similar outbreak in the US leaving three people dead.

Dr. Redinbo, PhD in biochemistry and biophysics, from the University of North Carolinaat Chapel Hill made an astounding discovery in his lab. He tested some of the older medications used for osteoporosis treatment, the biphosphonates clodronate and etidronate, to see whether they would have an effect on stopping the multiplication of these harmful bacteria. Dr. Redinbo’s work was published in the July 13 edition of the Proceedings of the National Academy of Sciences. Dr. Redinbo’s team found that an enzyme, called relaxase, is at the center of the development of antibiotic resistance. When resistance develops, there is a genetic transformation that takes place, like a mini Darwinian selection process where the most resistant bacteria survive and multiply. The resistant bacteria mate with each other and with bacteria that are not yet resistant. This process involves the relaxase enzyme system, some DNA stranding and a strand exchange. In this way new resistant bacteria are formed. Experiments under the supervision of Dr. Redinbo found that this process can be stopped by the phosphate-rich compound, biphosphonates (clodronate and etidronate). Other chemicals were found to not be as effective.

New Cure For Drug Resistant Bacteria At The Horizon

New Cure For Drug Resistant Bacteria At The Horizon

The relaxase system is found in a number of problem bacterial strains, Staphylococcus strains, drug resistant Acinetobacter strains and others. Unfortunately the biphosphonates have some side-effects like stomach soreness and birth defects. The researcher said that he hopes that these drugs and perhaps others with less side-effect will offer new treatments for antibiotic resistant bacteria.

Reference: July 13, 2007 edition of the Proceedings of the National Academy of Sciences

Last edited December 5, 2012