Potential novel antibiotics under review

Despite my dire announcements regarding the potential challenges in treating infectious diseases in the near future, which are coming about due to a combination of biological and economic reasons, there are some reasons to be somewhat optimistic. Via Microbe, the monthly newsletter from the American Society of Microbiology, an article which summarizes some of the research into novel antibiotics that are currently in clinical trials. The article lists at least 39 potential antibacterial compounds under investigation at present, with 25 of those under what is termed Phase 2 or Phase 3.  In Phase 2 or Phase 3 trials, the compounds have shown promise in in vitro or animal models, have been found to be safe to administer to humans, and therefore are being assessed to see if they show therapeutic promise in humans. Leading the search for new antimicrobials are small biotech companies such as Cubist here in the US, and the large company Hoffman-La Roche from Switzerland.

One of the very interesting targets is an enzyme called DNA topoisomerase, which catalyzes the unwinding of DNA during the process of DNA replication. Many of these compounds are from the quinolone class of antimicrobials, some of which are easily taken up into host cells, thereby allowing them to be effective against intracellular pathogens such as Legionella pneumophilia and Mycoplasma pneumoniae. The target of these compounds are enzymes that are found in all cells, including human cells, however they are able to demonstrate the principle of selective toxicity by inhibiting the prokaryotic enzymes as opposed to eukaryotic enzymes. Some studies have described side effects where the DNA replication of mitochondria can be inhibited as well.

Other important antimicrobial compounds under investigation inhibit protein synthesis, and a number of compounds are currently under intense review for effectiveness. Some of these compounds have been identified by manipulating known antimicrobials (semi-synthetic compounds) or are the result of new compounds identified by screening environmental microorganisms for inhibitory compounds.

One of the major problems due to antibiotic use in appropriate situations is the rise in other infections, which arise as the normal microbial flora are reduced by the use of the antibiotic. Clostridium difficile infections are increasing in frequency at present, and are themselves beginning to demonstrate antibiotic resistance. Several new compounds under investigation appear to target C. difficile infections very specifically, enabling them to be much more effective against the pathogen in question, while having little effect on other microbes. This approach will help to forestall the emergence of other antibiotic resistance microorganisms, at least for a while.

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Notes from the Field: Listeria from Soft-ripened cheese

 

some nice cheese, via Cheese.com

some nice cheese, via Cheese.com

Via the ever helpful Morbidity Mortality Weekly Report, another alert about the dangers of foodborne-illness! The Minnesota Department of Health reported in late July 2013 two cases of invasive listeriosis, for which molecular analysis indicated a sole-source for infection. As an aside, the Minnesota Department of Health seems to be the hardest working state department of health, as evidenced by this alert about Salmonella from Guinea pigs, and this alert about Salmonella from phlebotomy that I found in the BIO230 archives. Way to go, Minnesota Department of Health!

Once the Centers for Disease Control and Prevention were notified, further analysis indicated that the isolate was also identical to an environmental isolate collected from a cheese producer in 2011. With this in place, several other cases were also identified by the CDC in last summer’s outbreak, resulting in one death and one miscarriage. All patients were interviewed to determine their “cheese exposure.” All patients indicated that they had likely eaten one or more of Crave Brothers Farmstead Cheese varieties (Les Frères, Petit Frère, or Petit Frère with truffles) during the likely time frame for infection, at either grocery stores or restaurants in the region. All of the cheeses were shipped as intact wheels to the point of sale, where they were cut and repackaged.

The manufacturer issued a voluntary recall when news of the outbreak was made public. Conjecture by the CDC suggested that the contamination arose during the manufacturing process. The process of pasteurization very effectively eliminates Listeria monocytogenes from milk, however in the cheesemaking process contamination can occur after the original pasteurization. The CDC recommends that strict sanitation and monitoring of contamination steps always be in place for cheesemakers, regardless of whether pasteurized milk is used.

The CDC also reiterated standard precautions to protect against infection by Listeria, which again bear repeating. The organism does not generally pose a significant health risk to the general population, however immunocompromised individuals can become quite seriously ill. Additionally, pregnant women can pass the organism onto the developing baby, and fetal infection due to Listeria is a significant cause of miscarriage. Because of these risks, at risk individuals are strongly advised to avoid any food that carries the potential for infection by Listeria.

Issues in the fight against antibiotic resistance

Development of new antibiotics versus appearance of resistant bacteria

Development of new antibiotics versus appearance of resistant bacteria

I apologize for the slow pace of updates this semester; it has been hectic, and scouring the news for alerts of general microbiological interest to post here has taken a backseat to grading for the past few weeks. However, I came across a review article from the latest issue of Trends In Microbiology that is timely with regards to our current class discussion about antibiotics and their place in modern medicine.

I have painted a less than rosy picture many times in this forum about the future of medicine, primarily as a result of the diminishing utility of antibiotics. The premise is this: the more antibiotics are used to treat infectious disease, the less they are ultimately effective as a result of the acquisition of antibiotic resistance. Indeed, the observation that genes conferring antibiotic resistance to today’s antibiotics have been found in thousands of years old samples of bacteria in permafrost suggests that acquisition of resistance is not a matter of “if it happens,” but rather “when it happens” to antibiotics that haven’t even been developed yet.

In our viewing of the Frontline episode “Hunting the Nightmare Bacteria” in class the other day, one of the most alarming points come out to me was the highlighting of the problem of who is supposed to deal with with looming catastrophe. The majority of the large pharmaceutical companies have pulled out of the antibiotic business due to a simple financial decision–it costs a tremendous amount of money to bring new drugs to market, and by their nature antibiotics give a very poor return on investment. At the same time, it was also clear that there is no national consensus to determine the scope of the problem or what the most appropriate response should be.

The review article takes the following stance; public health officials must be proactive in recognizing the severity of the issue, and governments need to take the lead in prioritizing antibiotic discovery in both academic and industrial settings. Public-Private partnerships (PPPs) have been established in small scale between not-for-profit charities, small biotech companies, and large pharmaceutical firms, however the lack of financial return has limited their effectiveness to date. The model however is valid, and if adopted large scale the financial burden of bringing these critical drugs to market can be distributed broadly between the academic, governmental, and industrial players. Such a model in the current political climate in the United States is difficult, but not impossible to propose. These organizations have successfully come into being in Europe which has traditionally had a more open interaction between government and industry, however the passing in the US of the Prescription Drug User Fee Act (PDUFA V) provides financial incentives for novel antibiotic development in this country. Hopefully, these incentives will allow medicine to stay ahead of antibiotic resistance at least for a little while!

Pain relievers the new superheroes against the fight of bacterial infection

Inhibition of bacterial DNA synthesis by NSAIDs

Inhibition of bacterial DNA synthesis by NSAIDs; image via Cell Press

One of the major issues that health care will be facing is the decreasing effectiveness of antibiotics against infectious disease. The ability of microorganisms to become resistant to many different antibiotics is expensive, and leads to increased mortality to many infections that have previously been easily treatable. Sherrell Carter (11 AM Micro) found an article from the medical journal Chemistry and Biology that reports an “outside the box” type of idea; some common anti-inflammatory drugs used to treat aches and pains also have effects on microorganisms, and this might be exploited to treat infections due to those organisms. Here is Sherrell’s summary:

Amazing how certain commonly over the counter drugs that aid daily Americans in their struggles against aches, pains, fever, and inflammation are also believed to have the ability to eradicate bacteria and prevent infection. Innovative research at the University of Wollongong, in Australia  suggest  that these  drugs, better known as nonsteroidal anti-inflammatory drugs, act on bacteria in a way that is incorrigibly different from current antibiotics. This discovery could provide new developments for fighting drug-resistant infections and ‘superbugs that pose a threat on human health.

Scientist has discovered that some anti-inflammatory drugs used in human and veterinary medicine have weak antibiotic activity and that they prevent bacteria from copying their DNA, needed for replication.   Dr. Aaron Oakley of the University of Wollongong, in Australia analyzed three NSAIDs: bromofenac, carprofen, and vedaprofen. I’m flabbergasted to know that a class of meds that can be found in our medicine cabinet are among pharmaceutical residences like aspirin, ibuprofen, and naproxen, impairing the proper functioning of bacteria’s DNA.

I was bewildered by Dr. Oakley and his team ability to recognize that anti-inflammatory drugs can bind to and inhibit a specific protein in bacteria called the DNA clamp. Our common everyday over counter drugs have an amazing benefit to our immune system. It was noted in the study that DNA clamp, is an enzyme that synthesizes DNA molecules from their nucleotide building blocks across various bacterial species.

Subsequently, it’s amazing to feel excitingly ahead the race of bacterial infections and retired overused antibiotics. But as we race to our local pharmacy for over the counter assistance’s we may need to exercise a little patience’s before we can claim an instant cure. Nevertheless, carprofen, vedaprofen and bromfenac require additional testing before it can be prescribed precisely as an antibiotic.

Gene Editing Fights HIV

New Picture (11)Holly Ortman (11 AM Micro) found an article on the BBC News website about a recent breakthrough in HIV therapy. Long time readers of BIO230 have seen the ups and downs in potential therapies for this disease. Here is Holly’s summary:

More than 1.1 million Americans are infected with HIV while 1 in 6 of those are not aware they are carrying the virus. The number of new infections is steadily increasing by more than 50,000 people per year. HIV has the tendency to progress into AIDS, which approximately 636,000 Americans have died since the beginning of the epidemic (stats from the CDC).

The gay, bisexual, and other men who have sex with men (MSM) remain the highest at risk group. Intravenous drug users and heterosexuals also continue to be affected HIV.

In a small but promising studying, “Doctors used gene therapy to upgrade the immune systems of 12 patients with HIV to help shield them from the virus’s onslaught.” (BBC News, p. 1) The patients’ white blood cells were removed, edited with HIV resistance, and injected back into the patient.

A small percentage, 1%, of the Caucasian population is born with a rare mutation that protects them from HIV. The mutation changes their T-cell structure so the virus cannot attach and multiply. The first patient to be cured of HIV, Timothy Ray Brown, had his immune system destroyed by leukemia treatment and received a bone marrow transplant from a donor with the mutation.

Researchers at University of Pennsylvania changed the 12 patient’s immune systems by editing the DNA inside the T-cells to give them the CCR5-delta-32 shielding mutation. The patient’s T-cells were removed and grown in the laboratory. Once scientists had enough T-cells, about a billion, they incorporated the mutation and infused the cells back into the patient. Even though the researchers had a large number of T-cells, successful incorporation was only about 20%.

After four weeks of being off medication, blood samples were drawn from the patients and T-cell numbers were counted. They found that the number of unchanged T-cells fell whereas the modified T-cells were protected and remained in the blood even after being off medication for one month.

According to Prof. Bruce Levine, director of the Clinical Cell and Vaccine Production Facility at the University of Pennsylvania, this type of gene therapy was very new and had not been successfully used in human trials until now. The purpose was to show that this type of technology was safe and viable. Researchers continue to work on gene therapy to remove the need for expensive daily HIV medications. There is still no idea of how long gene modification will last when it comes to fighting HIV. It isn’t seen as a viable option for initial drug therapy upon diagnosis but very possibly as drug choice later into the disease.

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