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September 2013 Archive

Posted by Chris on September 5th, 2013  ⟩  0 comments

The search for new antibiotics goes on and the accepted norm seems to be keeping our eyes narrowly focused on the bacteria that pervade our lives day in and day out. That’s a great idea, of course. Bacteria out number us probably along an order of 1 billion to 1. But what if there are other sources of antibacterial agents in the world, ones that haven’t been played out, and ones which just might provide new and/or unique mechanisms of action against the diseases that plague us?

For several years now, Luis Kanzaki’s team has been looking very closely into the jungle that surrounds them. With so much of the Amazon still to be “discovered” by Western science, it can still be very beneficial to look to their local, indigenous remedies for clues to new chemicals or drugs that may prove efficacious against some of our more dangerous pests. Every few years, researchers from Kanzaki’s lab in Brazil have published antimicrobial studies using locally known plants and trees which have typically been used to treat maladies from arthritis to sore throats to malaria. António Correia wrote papers in 2008, in which they found numerous, potentially new sources of antibiotics from plant extracts which were effective against several multi-drug resistant bacteria and again in 2010, where they discovered the presence of many of these same bacteria playing a part in the corrosion of metals of local dams and were able to inhibit their growth using similar plant extracts.

Antimicrobial activity of Amazonian plantsMore recently, Amanda Oliveira et al. found more Amazonian medicinal plant extracts to search for antimicrobial activity. Running a type of Kirby-Bauer diffusion assay (click here to find a GoldBio instructional video), they tested their extracts against gram-positive (such as E. coli, Salmonella enterica and Pseudomonas aeruginosa) and gram-negative (such as Staphylococcus aureus and Enterococcus faecalis) bacterial strains as well as the yeast C. albicans. Their results are striking! Several of their extracts performed 40-50% as efficacious as the control drug, Ciprofloxacin, a second generation fluoroquinolone antibiotic. One extract, Ptychopetalum olacoides, outperformed the control against Klebsiella ozaenae, a multidrug resistant, gram-negative bacteria. That’s an amazing success if you consider that these are crude extracts going up against a widely used, synthetic, broad-spectrum antibiotic.

Of course, the active ingredients in these extracts still need to be teased out, tested and optimized. So it’s not as if these are ready to use antibiotics. Regardless though, opportunities like these don’t come around every day. And in our current world in which more bacteria are becoming resistant and less antibiotics are making it to market, it makes me wonder what other discoveries await us if we were to but look around our own little jungles for something interesting.
 
 

Oliveira, A. A., Segovia, J. F., Sousa, V. Y., Mata, E. C., Gonçalves, M. C., Bezerra, R. M., Junior, P. O., & Kanzaki, L. I. (2013). Antimicrobial activity of amazonian medicinal plants. SpringerPlus, 2(1), 1-6.

Correia, A. F., Segovia, J. F. O., Gonçalves, M. S. A., De Oliveira, V. L., Silveira, D., Carvalho, J. C. T., & Kanzaki, L. I. B. (2008). Amazonian plant crude extract screening for activity against multidrug-resistant bacteria. Eur Rev Med Pharmacol Sci, 12(6), 369-380.

Correia, A. F., Segoviae, J. F. O., Bezerra, R. M., Gonçalves, M. C. A., Ornelas, S. S., Silveira, D., Carvelho, J. C., & Kanzaki, L. I. B. (2010). Aerobic and facultative microorganisms isolated from corroded metallic structures in a hydroeletric power unit in the amazon region of Brazil.

Category Code: 79101


Posted by Chris on September 12th, 2013  ⟩  0 comments

Stepping back briefly from the antibiotic discussion on growing resistance and the veritable nose dive of new discoveries, I found that there are actually several alternative methods currently in research that are not only promising but may also change the way we look at fighting bacterial infection.

From the beginning, antibiotics were always viewed as more of a golden, magical pill from some fairy tale than anything. “If you take this golden pill, everything will be perfect and you will live happily ever after!” The early warnings of immanent resistance from the premier scientists who discovered them went unheeded, unheard. There would always be another golden pill, another miraculous cure-all, and life would go on forever without worry. Don’t worry! Science would make it all OK. It was a naïve and fragile pedestal we built and one that came crashing down just as expected.

Facing this cliff of impending antibiotic doom, many scientists agreed that what was needed was not the search for another “magical” cure, but a better understanding of the process of virulence itself. And with that understanding, maybe something in the process itself can be found that is vulnerable. This isn’t a cure-all, however. The expectation is that every virulent agent is different and there might be dozens of alternate processes and modes-of-action, if not more. But if we can learn how the processes works, then we might be able to more accurately target the problem, like using a laser to cut a string rather than our typical approach of an antibiotic cruise missile. Because, while most antibiotics still function in destroying the majority of bacterial maladies, they also wreak havoc and destruction on the vital, internal microbiota that we generally take for granted until it’s gone. It’s the equivalent of bombing Paris to kill the rats.

Several years ago, Lynette Cegelski and a small group from Washington University of St. Louis published a comprehensive review of some of those alternative therapeutic fields; including Quorum sensing, secretion system targeting, and microbial attachment. It is a very good review and well deserving of a read through if you haven’t looked at it already. Yesterday, Ji Yang et al. published a paper in the Journal of Biological Chemistry, which delved into the use of chemical inhibition of the gene expression of the bacteria Citrobacter rodentium. C. rodentium is a mesophilic, gram-negative bacterium which causes severe behavioral changes and diarrhea in mice and is the equivalent of an E. coli infection in humans. Yang targeted the AraC family of regulators which controls the transcription of genes involved in carbon metabolism, stress response and pathogenesis.

Regacin DNA Binding domainSimilar to a previous study on ToxT proteins from Vibrio cholerae from Deborah Hung et al. in 2005, Yang screen nearly 12,000 compounds for RegA inhibitors to identify 13 positive compounds. They focused on one compound that completely inhibited the β-gal activity of the test strain, discovered a variant of the chemical which had even more efficacy, and nicknamed it “Regacin”. They reported that regacin actively inhibited C. rodentium’s toxic effects both when administered before inoculation as well as 12 hours after inoculation! Regacin works by interacting directly with the double HTH domain of the molecule, but did not hinder the dimerization of the DNA as did the small molecules from Hung’s research. It also did not have any effect on the rest of the microbiota. Yang further discovered that C. rodentium did not have any effect on the mice when delivered directly to the large intestine. So, by inhibiting its ability to react to conditions in the small intestine, the bacteria is then able to pass harmlessly through the host without becoming virulent. However, the down side is that regacin only seemed to affect some of the RegA targets, such as Rns and RegR, but not others, like AggR or ToxT.

 
So clearly, this is only the beginning of something promising. But it IS promising, nonetheless.

 
 

Yang J, Hocking DM, Cheng C, Dogovski C, Perugini MA, Holien JK, Parker MW, Hartland EL, Tauschek M, Robins-Browne RM. (2013) Disarming bacterial virulence through chemical inhibition of the DNA-binding domain of an AraC-like transcriptional activator. J Biol Chem. Sep 9. [Epub ahead of print].

Cegelski, L., Marshall, G. R., Eldridge, G. R., & Hultgren, S. J. (2008). The biology and future prospects of antivirulence therapies. Nature Reviews Microbiology, 6(1), 17-27.
Hung, D. T., Shakhnovich, E. A., Pierson, E., & Mekalanos, J. J. (2005). Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science, 310(5748), 670-674.

Hung, D. T., Shakhnovich, E. A., Pierson, E., & Mekalanos, J. J. (2005). Small-molecule inhibitor of Vibrio cholerae virulence and intestinal colonization. Science, 310(5748), 670-674.

Category Code: 79102 79101

Posted by Chris on September 19th, 2013  ⟩  0 comments

There are a lot of things that humans believe that they have invented or discovered that just isn’t true at all. When our ancestors were first contemplating the domestication of cattle or goats as a source of meat and milk, some ants had already been raising aphids (corralling them, nurturing them and living off their “milk”) for millennia. Now, in a paper from the Proceedings of the Royal Society, Thomas Chouvenc has discovered that even our systematic use of antibiotics isn’t actually all that novel.

Formosan subterranean termites (Coptotermes formosanus) are one of the most destructive species of termites in the world. Originating from China and then hopping over to Taiwan, where they received their name, they have now been inadvertently introduced into Japan, Hawaii, South Africa and the United States. A mature colony can contain several million termites and can consume nearly a pound of wood every day, foraging an area of over 70,000 square meters! At that rate, they can practically destroy a house in a matter of months and no established colony of Formosan termites has ever been successfully eradicated.

The Formosan termites build a sponge-like structure within the galleries of their colony which is a composite mix of wood particles and faecal material, usually called “carton material”. The carton is instrumental in stabilizing the colony structure as well as helping maintain temperature and moisture level within the colony. But with relatively high temperatures and moisture, there is also a higher probability of fungal or bacterial infections in the colony as well. Metarhizium anisopliae is just such a fungal pathogen. M. anisopliae is a naturally occurring parasitoid that lives in soils throughout the world. It is known to infect over 200 species of insects, including termites, and has been used as a biological insecticide against a number of such pests. However, to date, Formosan termites have remained relatively immune to such challenges and Chouvenc now understands why.

Formosan TermitesChouvenc’s group found about 500 Actinobacteria isolates from 5 different Formosan colonies and over 70% of those isolates showed in vitro antimicrobial activity against a range of gram negative and gram positive bacteria, yeast, and fungi. The most common isolate was Streptomyces, the source of many of our most popular antibiotics, including Streptomycin, Chloramphenicol, Puromycin and Tetracycline. These naturally occurring bacteria, with their antibacterial components, effectively provide resistance to the termites for many of the pathogens they encounter inside their colonies. Chouvenc found that the termite’s faecal lining of the carton material in the foraging galleries acted as a perfect niche for the colonization of microorganisms like Actinobacteria and that colonies which had access to Streptomyces when infected with M. anisopliae had a significantly higher survivability than colonies which lacked Streptomyces.

One limitations of Chouvenc’s research was that all five colonies were derived from Florida, where Formosan termites are an invasive species. So there’s more research to be done to discover if this was a localized recruitment event post invasion or if this was an inherited trait of the native species.

The most fascinates part of this discovery for me is the way in which these termite colonies thrive in the presence of their natural antibiotics. Imagine if we were to coat not only our clothes, but our houses, linens, beds, chairs, tables etc. with a profusion of antibiotics all the time. Experience has shown us that we would be (and are!) inundated with larger numbers of resistant varieties of our pathogens from such overuse. In fact, the CDC just posted a news bulletin highlighting this issue exactly.

But here we have termites who are seemingly able to bypass that natural tendency and survive! This is a bigger question than simply, “How can we use this knowledge to eradicate this pest”. Instead, we should be asking: How can we learn from these creatures to use our antibiotics more prudently and effectively? How can we continue to use the same antibiotics over a long period of time, overcoming the threat of resistance and antibiotic failure? These bugs seem to have been doing this, effectively, for millions of years…there is still so much for us to learn.

 
 

Chouvenc, T., Efstathion, C. A., Elliott, M. L., and Su, Nan-Yao (2013). Extended disease resistance emerging from the faecal nest of a subterranean termite. Proceedings of the Royal Society B, 280: 20131885.

Category Code: 79102 79101 88221

Posted by Chris on September 26th, 2013  ⟩  0 comments

(* Antibiotic Resistance Apocalypse)

Over the last several weeks, I’ve been discussing the greater concern over the increasing resistance of our current medicines and our lack of emerging antibiotics in the pharmaceutical industry. As I close out this month of blogs, I’d like to visit one more time with a couple of recent articles which discuss where we are as well as where we really need to be regarding new antibiotics.

The Infectious Disease Society of America (IDSA) is very concerned with the development and increasing resistance to antibiotics. In 2010, the IDSA issued a challenge to the US government and big pharma: develop and get regulatory approval for 10 new, safe and effective antibiotics by 2020, i.e. the “10 x ’20” initiative. The ultimate goal was to “support the development of 10 new systemic antibacterial drugs through the discovery of new drug classes as well as exploring possible new drugs from existing classes of antibiotics.” To help the push, many other organizations also endorsed the collaborative effort, including: the American Academy of Pediatrics, American Gastroenterological Association, Trust for America's Health, Society for Healthcare Epidemiology of America, Pediatric Infectious Disease Society, Michigan Antibiotic Resistance Reduction Coalition, National Foundation for Infectious Diseases and the European Society of Clinical Microbiology and Infectious Diseases.

Earlier this year, two groups posted their reviews of our current situation. Writing on behalf of the IDSA, Helen Boucher et al. summarized the progress of the development of new drugs which are active against Gram-Negative Bacilli (GNB) since 2010 and later, in the Annals of Clinical Microbiology and Antimicrobials, Matteo Bassetti et al. wrote a comprehensive summary of the antibiotics we are developing or have developed over the last 10 years.

BigPharma Antibacterial PipelineBoucher identified just 7 parenteral drugs that are in clinical development for treatment of infections caused by MDR (Multi-drug resistant) GNB and one other drug whose phase 2 trial has been halted. Of those 7 antibiotics, 4 are β-lactam plus β-lactamase inhibitor combination drugs. While that may be a great way to enhance the therapeutic options of this class of drugs, not one of these drugs demonstrated activity against the entire spectrum of clinical GNB. Even worse, only 5 of the top 11 major pharmaceutical companies had drugs in clinical trials and there were only 4 drugs in phase 2/3 trials that showed promise against either GNB or GPB (Gram-Positive Bacilli). Of course, the current trend of pharmaceutical companies seems to be to leaving the initial discovery and early testing to smaller biotechnology companies, so there is some hope that hidden discoveries are still underway. There is also some hope as various government leaders have begun to focus on the continuing crisis. But we need to get products moving now in order to fulfill the 10 x ’20 goal in just 7 short years.

Bassetti catalogued nearly 30 antibiotics that have been developed recently as tie-in to Boucher’s paper. There is more that is hopeful in this summarization, including 11 drugs which are in Phase 3 trials (9 of which are primarily against GPB). But only one of these, the combination of Ceftazidime/Avibactam is primarily targeted against MDR. Perhaps more importantly however, there are another 11 drugs which are currently in Phase 2 trials, and 3 in Phase 1 trials that are specifically targeting GNB or MDR. Only time will tell if these will prove to have the efficacy that we need as well as benignancy in regard to inadvertent side effects.

Developing Antibiotics

Ultimately, I believe there is hope for us, although the significant hurdles of regulatory approvals remain. The IDSA is helping to push for clearer regulatory guidance in the study of antibiotics, working with the FDA for more urgent approval of pathogen-specific clinical trials and the creation of a new FDA approval pathway for limited-population antibacterial drugs. But if overly-complicated approval pathways and the potential failure of profitability continue to haunt the pharmaceutical companies which are necessary to bring these drugs to us, our ARA doomsday clock may strike Midnight far sooner than we think.

 
 

Boucher, H. W., Talbot, G. H., Benjamin, D. K., Bradley, J., Guidos, R. J., Jones, R. N., & Gilbert, D. (2013). 10×'20 progress—Development of new drugs active against gram-negative bacilli: An update from the infectious diseases society of america. Clinical Infectious Diseases, 56(12), 1685-1694.

Bassetti, M., Merelli, M., Temperoni, C., & Astilean, A. (2013). New antibiotics for bad bugs: where are we?. Annals of clinical microbiology and antimicrobials, 12(1), 1-15.

Category Code: 79102