Posts Tagged ‘Antibiotics’

Antibiotics – let’s clean up our act

Tuesday, May 27th, 2014
East Penobscot Bay, Maine by Jason Mrachina

Beautiful Penobscot Bay

Last week I wrote about a new type of antibiotic which targets bacteria in biiofilms. Ron Huber (Friends of Penobscot Bay) left an interesting comment:

“Of concern to us as … conservationists is whether these broad spectrum peptide antibiotics are digested by standard sewage treatment plant technology or pass essentially unscathed through the patient and the wastewater treatment facility and into the receiving waters. We want and absolutely need vigorous marine biofilms, an at a variety of scales and species mixes, if we are to have mussels, lobsters, clams, oysters and other organisms at all… Sewage plants are adaptable; can something be added that would bind with the antibiotic or otherwise render it harmless before discharge We would really like to know!” (full comment)

There has been much discussion about the misuse of antibiotics in agriculture and the impact of such careless use on human health. There has been rather less public discuss on on the environmental impact of antibiotic resides in sewage effluent. So apart from the environment, do antibiotic residues which survive sewage pose a risk to human health?

Yes they do (Selective pressure of antibiotic pollution on bacteria of importance to public health. (2012) Environmental health perspectives, 120(8), 1100). Consequently, there is a fair amount of research being carried out in this area – it just doesn’t make it into the press. Standard sewage treatment processes reduce but don’t eliminate antibiotics in sewage and these can contribute to the evolution and persistence of resistant pathogens in the environment (The effectiveness of sewage treatment processes to remove faecal pathogens and antibiotic residues. (2012) Journal of Environmental Science and Health, Part A, 47(2), 289-297). This paper shows that more advanced treatments such as membrane bioreactor technology reduce antibiotic resides more than the conventional activated sludge process, but still do not eliminate them completely from the wastewater.

What effect do these residues have on the environment? We really don’t know, but it seems likely that legislators are more likely to respond to the costs involved in improving sewage treatment via the human health argument rather than the environmental argument. Sad, but that’s how it is. As far as the new peptide antibiotic I wrote about last week is concerned, we simply don’t know yet how it will be affected by sewage treatment processes. But should we be worried about such criteria when introducing new compounds for therapeutic use? Yes we should. Of course, it’s not just antibiotics we have to worry about.

 

New Broad-Spectrum Peptide Antibiotic Targets Biofilms

Friday, May 23rd, 2014

Biofilm Biofilms are structured multicellular communities of microorganisms associated with surfaces. They have been widely studied, in part because they cause at least 65% of all human infections, being particularly prevalent in device-related infections, on body surfaces and in chronic infections. Biofilms represent a major health problem worldwide due to their resistance to host defence mechanisms and to conventional antimicrobials, which generally target free-swimming (planktonic) bacteria. So there is an urgent need to identify compounds that effectively clear biofilm-related infections.

A new report in PLoS Pathogens identifies a potent anti-biofilm peptide that works by blocking (p)ppGpp, an important signal in biofilm development. The peptide had at least three effects on biofilms, which might reflect the role of (p)ppGpp in cells. First when added prior to initiation of biofilms it prevented biofilm formation, second it specifically led to cell death in biofilms at concentrations that were not lethal for planktonic (free-swimming) cells, and third it promoted biofilm dispersal even in maturing (2-day old) biofilms. This anti-biofilm strategy represents a significant advance in the search for new agents that specifically target many bacterial species.

 

Broad-Spectrum Anti-biofilm Peptide That Targets a Cellular Stress Response. (2014) PLoS Pathog 10(5): e1004152. doi:10.1371/journal.ppat.1004152
Bacteria form multicellular communities known as biofilms that cause two thirds of all infections and demonstrate a 10 to 1000 fold increase in adaptive resistance to conventional antibiotics. Currently, there are no approved drugs that specifically target bacterial biofilms. Here we identified a potent anti-biofilm peptide 1018 that worked by blocking (p)ppGpp, an important signal in biofilm development. At concentrations that did not affect planktonic growth, peptide treatment completely prevented biofilm formation and led to the eradication of mature biofilms in representative strains of both Gram-negative and Gram-positive bacterial pathogens including Pseudomonas aeruginosa, Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, methicillin resistant Staphylococcus aureus, Salmonella Typhimurium and Burkholderia cenocepacia. Low levels of the peptide led to biofilm dispersal, while higher doses triggered biofilm cell death. We hypothesized that the peptide acted to inhibit a common stress response in target species, and that the stringent response, mediating (p)ppGpp synthesis through the enzymes RelA and SpoT, was targeted. Consistent with this, increasing (p)ppGpp synthesis by addition of serine hydroxamate or over-expression of relA led to reduced susceptibility to the peptide. Furthermore, relA and spoT mutations blocking production of (p)ppGpp replicated the effects of the peptide, leading to a reduction of biofilm formation in the four tested target species. Also, eliminating (p)ppGpp expression after two days of biofilm growth by removal of arabinose from a strain expressing relA behind an arabinose-inducible promoter, reciprocated the effect of peptide added at the same time, leading to loss of biofilm. NMR and chromatography studies showed that the peptide acted on cells to cause degradation of (p)ppGpp within 30 minutes, and in vitro directly interacted with ppGpp. We thus propose that 1018 targets (p)ppGpp and marks it for degradation in cells. Targeting (p)ppGpp represents a new approach against biofilm-related drug resistance.

 

The battle against TB

Tuesday, December 3rd, 2013

The Guardian I have written a lot on MicrobiologyBytes about tuberculosis (TB) as a remerging disease, but the global TB situation is still poor, so it’s always worth bringing this issue to people’s attention again. Writing in The Guardian, Nick Herbert points out the painfully slow progress which has been made (The fight against TB is not over):

The rate of new cases of TB has been falling worldwide for about a decade, enough to hit a UN millennium development goal target, and deaths will have nearly halved since 1990. But a decline of 2% a year in the estimated incidence rate suggests that the disease is being beaten at a shamefully slower rate than when the west tackled it a century ago. On current progress it will take at least another 100 years. The latest World Health Organisation report, published last month, warned that 3 million people a year who develop TB are being missed by health programmes. Most worryingly, less than a quarter of drug-resistant cases are being detected and less than half of those that are detected are successfully treated.

So hats off to Mr Herbert for highlighting this important issue. But this is The Guardian, and the byline to this story includes the phrase “western leaders need to act now“. Mr Herbert points out that:

London has the highest rates of TB of any city in western Europe. The borough of Newham has rates equivalent to Nigeria.

All of which is true. Commenters on The Guardian article weren’t slow to mention that Nick Herbert is a serving Tory MP, who was previously director of public affairs at the British Field Sports Society for six years. While the editorial process at The Guardian has ensured that the facts in Mr Herbert’s article are correct, it’s hard to disentangle this piece from the Tory agenda on limiting immigration and the aftermath of the failed badger cull.

So yes, we need to do more about TB, as some of us have been pointing out for years. But we also need to be critical and questioning about where we acquire information and how we react to it. Politicians and science generally don’t mix. On the whole, that’s a good thing – there’s already too much politics in science.

 

Life in the Post-Antibiotic Era

Thursday, November 7th, 2013

Record-High Antibiotic Sales for Meat and Poultry Production Last week I was struck by this article in The Verge, Dead meat: how to raise livestock in a post-antibiotic era. I was particularly interested in this because only a week earlier I had been teaching our first year students about emerging infectious diseases and the growing feeling that we are entering the post-antibiotic era. As this paper published in 2005 put it:

“The indiscriminate and inappropriate use of antibiotics in outpatient clinics, hospitalized patients and in the food industry is the single largest factor leading to antibiotic resistance. In recent years, the number of new antibiotics licensed for human use in different parts of the world has been lower than in the recent past. In addition, there has been less innovation in the field of antimicrobial discovery research and development. The pharmaceutical industry, large academic institutions or the government are not investing the necessary resources to produce the next generation of newer safe and effective antimicrobial drugs. In many cases, large pharmaceutical companies have terminated their anti-infective research programs altogether due to economic reasons. The potential negative consequences of all these events are relevant because they put society at risk for the spread of potentially serious MDR bacterial infections.”
Alanis, A. J. (2005) Resistance to antibiotics: are we in the post-antibiotic era? Archives of medical research, 36(6), 697-705

The medical profession has rightly received a lot of criticism for undermining antibiotics by handing them out far too freely for trivial infections which though inconvenient, are self-limiting. That situation is now largely historic, and in most countries over-prescribing of antibiotics has ended, or at least decreased, although it is still worrying that in some countries antibiotics are still available without prescription to anyone who can afford to buy them. But medics don’t deserve a fraction of the criticism due to the worst offenders – the agricultural industry, where antibiotics have been used for decades as “growth promoters” in livestock production. The term “growth promoter” means that these valuable compounds are not being used for animal welfare to treat veterinary infections – which is entirely justified – but in a blanket fashion to make animals put on weight faster so they can be sold at a younger age, increasing profit.

I first became aware of this problem many years ago when I was visiting a student on an industrial placement with a major pharmaceutical company who told me proudly about their production of growth promoters and how many thousands of tons and antibiotics they sold to farmers each year. The recent report from Johns Hopkins University puts this ongoing problem into perspective. After decades of this misuse, we are paying the price, with multidrug-resistant bacteria now common in foodstuffs.

For decades we kept ahead of this impending catastrophe by discovering and marketing new antibiotics, but that pipeline has essentially run dry. Although we may find a few useful new compounds from coral reefs or deep sea hydrothermal vents, we are having to admit that we can no longer run fast enough to outpace bacterial evolution. And as future prospects decrease, so economics pays us back.

“In many cases, large pharmaceutical companies have terminated their anti-infective research programs altogether due to economic reasons.”

This is not a problem that the free market is likely to solve. So where do we go from here? Personally I’m not optimistic about the prospects for probiotics making all our problems go away. I don’t think persuading cows to gargle garlic tea is going to save us at this point. So what will (if anything?). The only realistic hope I can see on the horizon is the application of nanotechnology to build new anti-infective compounds rather than relying on snatching them from nature. Realistically, that prospect is decades away. Less realistically, it is also not without risks, such as the grey goo scenario of runaway nano-machines which keeps Prince Charles awake at night.

So are we all going to die? Yes, of course we are – such is the nature of life. But we have a choice of how and when depending on how hard we work on the problem. If future generations of microbiologists can learn enough about the molecular mechanisms which pathogens need to function, then we will have the opportunity to build a new generation of nanobiotics which will keep us ahead of the bacteria. For a little while. But never forget that bacteria have been around a lot longer than we have, and they’re not about to give up just yet.

 

 

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

MicrobiologyBytes Weekly – timebombs, smarter antibiotic use and bacteriophages you’ve never even heard of

Thursday, October 24th, 2013

Alan Cann Welcome to the first edition of the new format MicrobiologyBytes!

In this week’s edition:

  1. Today is World Polio Day
  2. Antibiotics – have we got it all wrong?
  3. Unexploded device? The vCJD timebomb
  4. How science works
  5. The wonderful world of archaeal viruses
Today (October 24th) is World Polio Day 

In support of this event the UK Society for General Microbiology has published a useful document describing the fight against this disease – past, present and future – and the lessons it hold for other infections (free, and very useful for teachers and students).

Poliovirus
When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load 

Cancer is a difficult disease to treat, but great advances have been made in the past few decades, mostly coming from using drugs in combination rather than one at a time. Exactly the same drug combination approach works for HIV infection, although sadly it doesn’t provide a cure. As it becomes harder and harder to treat bacterial infections with the few remaining antibiotics which are still effective, we need similarly imaginative approaches to therapy. A new paper in PLOS Biology looks at combinations of different drugs that are purposefully used to produce potent therapies. Textbook orthodoxy in medicine and pharmacology states one should hit the pathogen hard with the drug and then prolong the treatment to be certain of clearing it from the host. If the textbooks are correct, a combination of two antibiotics that prevents bacterial growth more than if just one drug were used should provide a better treatment strategy. Testing alternatives like these, however, is difficult to do in vivo or in the clinic, so the authors examined these ideas in laboratory conditions where treatments can be carefully controlled and the optimal combination therapy easily determined by measuring bacterial densities at every moment for each treatment trialled. Studying drug concentrations where antibiotic synergy can be guaranteed, they found that treatment duration was crucial. The most potent combination therapy on day 1 turned out to be the worst of all the therapies we tested by the middle of day 2, and by day 5 it barely inhibited bacterial growth; by contrast, the drugs did continue to impair growth if administered individually. 

When the Most Potent Combination of Antibiotics Selects for the Greatest Bacterial Load: The Smile-Frown Transition. (2013) PLoS Biol 11(4): e1001540.

 

Unexploded device? The vCJD timebomb 

Over at the Principles of Molecular Virology blog, I’m publishing the updated content for the next edition of the book as I research it. Chapter 8 of Principles of Molecular Virology discusses subviral agents – viroids and prions responsible for diseases such as scrapie, BSE and CJD. So many facts about human prion disease remain unknown, but what is clear is that decades after it started, mad cow disease has not gone away – the effects of the outbreak will rumble on for decades to come. New data from the UK show that the previous estimate of the number of vCJD carriers was an underestimate, but what does the future hold for those exposed to BSE-infected food in the 1980s and 1990s?

Principles of Molecular Virology
Molecular structure of the HIV-1 envelope protein 

A group of researchers publishes a structure for the HIV-1 envelope protein complex – the crucial membrane-fusing molecular machine responsible for virus attachment and entry into host cells and which is the sole virus-specific target for neutralizing antibodies (Molecular architecture of the uncleaved HIV-1 envelope glycoprotein trimer. (2013) PNAS USA 110 (30): 12438-12443). You’d think people would be happy. But not everyone is. “You got it wrong” they say, or “Oh no it isn’t“. “We took you comments into account and we still believe we are right” say the original authors. “Look at this picture of Einstein” says the world’s leading expert in the field. This saga is a great illustration of how science really works and a warning for students and journalists who want to believe that there are simple right/wrong answers to complex questions and that we either know something or we don’t. A great example of how sciences inches closer to the truth one step at a time.

Einstein
The wonderful world of archaeal viruses 

Think you know about bacteriophages? You might be shocked at how much you have to learn. Most microbiologists are obsessed with “true bacteria”, to the virtual exclusion of the Archaea. That prejudice carries over to their viruses. This review [sorry this one requires a subscription - I try to avoid this whenever I can] presents a personal account of research on archaeal viruses and describes many new virus species and families, demonstrating that viruses of Archaea constitute a distinctive part of the virosphere and display structures that are not associated with the other two domains of life, Bacteria and Eukarya. Studies of archaeal viruses provide new perspectives concerning the nature, diversity, and evolution of virus-host interactions. Broaden your outlook – this one is well worth reading.

The wonderful world of archaeal viruses. (2013) Ann Rev Microbiol. 67: 565-585.

Bactriophage STIV2

 

Got any comments or questions about any of these items? Just let me know.

Enter your email address to subscribe to this blog and receive notifications of new posts by email.

Bacteria-eating viruses aid war on superbugs

Thursday, October 17th, 2013

University of Leicester researchers use phages to fight Clostridium difficile

Since the discovery of the first antibiotic – penicillin – antibiotics have been heralded as the ‘silver bullets’ of medicine. They have saved countless lives and impacted on the well-being of humanity. This was beautifully illustrated in Michel Mosley’s TV series Pain Pus and Poison this week. But less than a century following their discovery, the future impact of antibiotics is dwindling at a pace that no one anticipated, with more and more bacteria out-smarting and ‘out-evolving’ these miracle drugs. This has re-energised the search for new treatments, such as phages. The key advantage of using phages over antibiotics lies in their specificity. A phage will infect and kill only a specific strain/species of bacteria. This is particularly important when treating conditions like C. difficile infections:

More information

It’s a bacterium eat bacterium world

Wednesday, June 12th, 2013

Bacteria Bacteria communicate with one another via quorum-sensing signal molecules. This paper describes the first example of quorum-sensing molecules participating in interspecies bacterial cell death. This is an interesting observation in its own right – but think about this: these peptides potentially provide the basis for a new class of antibiotics which trigger death by acting from outside the cell.

 

Novel Quorum-Sensing Peptides Mediating Interspecies Bacterial Cell Death. (2013) mBio 4(3): e00314-13 doi: 10.1128/mBio.00314-13
Escherichia coli mazEF is a toxin-antitoxin stress-induced module mediating cell death. It requires the quorum-sensing signal (QS) “extracellular death factor” (EDF), the penta-peptide NNWNN (EcEDF), enhancing the endoribonucleolytic activity of E. coli toxin MazF. Here we discovered that E. coli mazEF-mediated cell death could be triggered by QS peptides from the supernatants (SN) of the Gram-positive bacterium Bacillus subtilis and the Gram-negative bacterium Pseudomonas aeruginosa. In the SN of B. subtilis, we found one EDF, the hexapeptide RGQQNE, called BsEDF. In the SN of P. aeruginosa, we found three EDFs: the nonapeptide INEQTVVTK, called PaEDF-1, and two hexadecapeptides, VEVSDDGSGGNTSLSQ, called PaEDF-2, and APKLSDGAAAGYVTKA, called PaEDF-3. When added to a diluted E. coli cultures, each of these peptides acted as an interspecies EDF that triggered mazEF-mediated death. Furthermore, though their sequences are very different, each of these EDFs amplified the endoribonucleolytic activity of E. coli MazF, probably by interacting with different sites on E. coli MazF. Finally, we suggest that EDFs may become the basis for a new class of antibiotics that trigger death from outside the bacterial cells.

Microbiology Today: Getting the message out

Sunday, June 9th, 2013



Microbiology Today: Getting the message out

The Society for General Microbiology (SGM) leads the way on antimicrobial resistance.

http://www.sgm.ac.uk/en/publications/microbiology-today/current-issue.cfm

Antibiotic alternatives in food-producing animals

Tuesday, April 9th, 2013

Antibiotics Alternatives to antibiotics are urgently needed in animal agriculture. The form these alternatives should take presents a complex problem due to the various uses of antibiotics in animal agriculture, including disease treatment, disease prevention, and growth promotion, and to the relative contribution of these uses to the antibiotic resistance problem. Numerous antibiotic alternatives, such as pre- and probiotics, have been proposed but show variable success. This is because a fundamental understanding of how antibiotics improve feed efficiency is lacking, and because an individual alternative is unlikely to embody all of the performance-enhancing functions of antibiotics. High-throughput technologies need to be applied to better understand the problem, and informed combinations of alternatives, including vaccines, need to be considered.

This article discusses alternative approaches to animal (and therefore human) health, such as:

  • Feed additives such as pre- and probiotics
  • Phage therapy
  • Vaccines
  • Mixing additives: potentiated probiotics and synbiotics

 

Treatment, promotion, commotion: antibiotic alternatives in food-producing animals. (2013) Trends Microbiol. 21(3): 114-119. doi: 10.1016/j.tim.2012.11.001