Alternative methods to antimicrobial chemotherapy for combating infectious disease do exist. In this article in Microbiology Today, Roy Sleator describes the role of probiotics in keeping pathogens at bay:
With life-cycles measured in minutes as opposed to years, bacteria have an extraordinary ability to evolve and adapt rapidly to changes in their environment. Thus, in a world where only the fittest survive, those bacteria which have developed resistance to antibiotics will predominate. This is particularly apparent in hospital environments where bacteria are in constant contact with many different antibiotics; such repeated exposure has facilitated the development of resistance to multiple antibiotics and what we now refer to as hospital acquired or nosocomial infections.
There are many options still available for new antibiotics. While the search for new drugs seems to be declining, in this article in Microbiology Today, Flavia Marinelli takes a look at the need for new antimicrobials:
Novel classes of antibiotics are constantly required due to the expanding population of patients at risk and the growing prevalence of resistant pathogens in hospital- or community-acquired infections. Despite this need, major pharmaceutical players seem to be reducing their efforts to discover new antibiotics. This is due to a combination of factors such as the maturity, great competition and increased genericization of the antibiotic market. Unrealized expectations from high-throughput screening, combinatorial chemistry and pathogen-genome-derived targets have also had a negative effect. The perception prevails that the discovery of novel antibiotics is a very rare event. On the other hand, past and present successes speak for a return to microbial product screening.
A recent paper in Trends in Microbiology examined the possibilities for using bacteriophages in controlling biofilms which might result in healthcare-associated infections (Preventing biofilms of clinically relevant organisms using bacteriophage. 2009 Trends in Microbiology 17: 66-72). Biofilms are firmly attached microbial communities in which the organisms produce an extracellular polymeric matrix. Biofilm organisms might cause disease by detachment of individual cells or clumps of cells, by production of endotoxin, or by providing a niche for the development of antibiotic-resistant organisms. Biofilm organisms are usually tolerant to antimicrobial agents and the treatment of indwelling medical device-associated infections with systemic antimicrobial agents is usually ineffective.
Bacteriophages have been used for the treatment of infectious diseases in plants and animals, although few clinical trials with stringent negative controls have been carried out. There is a renewed interest in phage therapy in light of growing concerns with antimicrobial resistance in healthcare institutions worldwide. The use of phages for the treatment of device-associated infections could reduce the use of antibiotics and might limit the spread of resistant organisms.
There is some evidence for the potential of phages in biofilm control. Bacteriophage T4 phage was effective against E. coli biofilms in a glucose-limited chemostat, although the rate of phage synthesis and assembly were directly proportional to the amount of protein synthesis in the host cell. Some phages produce polysaccharide depolymerases that have the potential to degrade the biofilm matrix.
Subscribe to podcasts (free):
[iTunes] Enhanced podcasts & videos
[RSS] mp3 podcasts (audio only) Play this episode:Enhanced version Audio only
However, there are several important characteristics of phage that should be considered when evaluating the potential of phages to control clinically relevant biofilms. The specificity of receptors for a single phage strain will determine its host range; some phage have specificity at the strain level, such as strain typing phages, whereas some are more broad-spectrum and can infect multiple strains or related species. This high degree of specificity could be a drawback, especially in the case of polymicrobial biofilms.
Few studies have explored the role of biofilms in the development of phage-resistance. Phage cocktails developed via the isolation of host range mutants and broad spectrum phage could be advantageous. Another important question is how a patient’s immune system will respond to the therapeutic introduction of phage. Phages are antigenic and elicit a response by serum antibodies and the cellular immune system. Repeated exposure to the phage results in increasing antibody titers and studies in animal models have shown that phage is cleared from the bloodstream by the cellular immune system. In a short-lived treatment, the antibody response to phage is weak except in cases were serum antibody titers are present before phage treatment. It is possible, although unproven, that phage might associate with biofilms and thereby be protected from inactivation. It might also be possible to design mutant phages with enhanced ability to resist clearance by the cellular immune system.
Antibiotics aren’t just for fighting infections. As Julian Davies describes in this article in Microbiology Today, they play a part in the bacterial signalling network:
Microbial products with antibiotic activity exhibit many other types of bioactivity; the word antibiotic describes a specific function, but the compounds are multifunctional. The fact that a particular product has inhibitory activity in the laboratory does not mean that it plays such a role in nature. Antibiotics have a number of effects on bacterial physiology; for example they may affect the ability to swarm or form biofilms, or act as mutagens and induce bacterial lysogens to produce phage. Less well appreciated is the fact that they also affect the function of plant cells and those of human hosts, and may cause undesirable side reactions; these secondary effects often occur at sub-inhibitory concentrations.
Researchers have identified two molecules that enable Escherichia coli (E. coli), the bacterium that causes many urinary tract infections (UTIs), to survive and reproduce, thereby providing possible new targets for antibiotic therapy. These molecules, siderophores, are iron-chelating compounds secreted by microorganisms. The new siderophores, yersiniabactin and salmochelin, were shown to allow disease-producing bacteria strains to steal iron from their hosts, making it easier for these bacteria to survive and reproduce. Their identification also presents a potential way to selectively eradicate the pathogenic E. coli strains without adversely affecting those strains that normally populate the gut.
UTIs are among the most common bacterial infections worldwide. Half of all women will experience a UTI at some point in their lives, and in 20 to 40% of these patients, the infection recurs. 90% of all UTIs are caused by E. coli, which may come from the human gut, where several strains of the bacteria reside. Some of those strains help their human hosts by aiding digestion and blocking other infectious organisms.
To study how friendly and infection-causing E. coli strains differ, researchers used a new approach called metabolomics. Instead of examining genes, metabolomics analyzes all the chemicals produced by a cell, which includes bacterial growth signals, toxins, and waste products. This allowed them to look at the end products of many genes working together. Bacteria studied in the experiment came from patients with recurrent UTIs. The researchers cultured E. coli from both stool and urine samples and found that the strains from urine made more yersiniabactin and salmochelin. Iron is an important nutrient typically kept under tight control by the host, and there is evidence that competition for iron has been raging for millennia between disease-causing microbes and the hosts they exploit. There may, however, be multiple ways to take advantage of the infectious bacterial strains’ reliance on siderophores. Researchers will try to block or disrupt the activity of the proteins that make siderophores, but they also may use a “Trojan horse” strategy. To steal iron, siderophores have to be sent out from the cell, bind to the iron, and then be taken back into the cell. If we can design an antibiotic that looks like a siderophore, we might be able to trick only disease-causing bacteria into taking up the drug while leaving other bacteria alone.
Quantitative Metabolomics Reveals an Epigenetic Blueprint for Iron Acquisition in Uropathogenic Escherichia coli. 2009 PLoS Pathog 5(2): e1000305
Bacterial pathogens are frequently distinguished by the presence of acquired genes associated with iron acquisition. The presence of specific siderophore receptor genes, however, does not reliably predict activity of the complex protein assemblies involved in synthesis and transport of these secondary metabolites. Here, we have developed a novel quantitative metabolomic approach based on stable isotope dilution to compare the complement of siderophores produced by Escherichia coli strains associated with intestinal colonization or urinary tract disease. Because uropathogenic E. coli are believed to reside in the gut microbiome prior to infection, we compared siderophore production between urinary and rectal isolates within individual patients with recurrent UTI. While all strains produced enterobactin, strong preferential expression of the siderophores yersiniabactin and salmochelin was observed among urinary strains. Conventional PCR genotyping of siderophore receptors was often insensitive to these differences. A linearized enterobactin siderophore was also identified as a product of strains with an active salmochelin gene cluster. These findings argue that qualitative and quantitative epi-genetic optimization occurs in the E. coli secondary metabolome among human uropathogens. Because the virulence-associated biosynthetic pathways are distinct from those associated with rectal colonization, these results suggest strategies for virulence-targeted therapies.
In 1928, by chance, Alexander Fleming discovered penicillin, which was subsequently developed and saved millions from death by infectious disease. In this article in Microbiology Today, Kevin Brown recounts the story of this amazing antibiotic and tells something of the man who found it:
In many ways Fleming could have only discovered the original wonder drug in his musty, dusty, overcrowded, cluttered laboratory at St Mary’s Hospital. After all, if there was no possibility of contamination there could have been no penicillin. Some might argue that without Fleming, there would have been none either. Certainly, the chance contamination of culture plates was common, but Fleming’s genius was to notice something unusual and act upon it. As a scientist, he was very much in the tradition of the 19th-century lone researcher interested in unusual phenomena. This approach was to pay dividends when in September 1928 he returned from a 6-week holiday to find not only that a plate of staphylococci, he had been working on before his holiday had become contaminated by a fungus, but that there was the now classic zone of inhibition around the mould. Ever the master of understatement, Fleming’s response was typical of the man: “That’s funny!”
Cholera is an infectious form of gastroenteritis caused by the enterotoxin-producing strains of the curved Gram-negative bacillus Vibrio cholerae. Transmission to humans occurs through ingesting food or water that is contaminated with faecal matter from infected people. Classically the disease occurs where there is a lack or failure of sanitation, e.g. in crowded urban conditions in developing countries or following natural disasters. In its most severe forms, cholera is one of the most rapidly fatal illnesses known – in some circumstances infected patients may die within hours if medical treatment is not provided. Usually the disease progresses from the first liquid stool to shock (due to dehydration) in 4 to 12 hours, with death following in 18 hours to several days, unless oral rehydration therapy is provided.
Subscribe to podcasts (free):
[iTunes] Enhanced podcasts & videos
[RSS] mp3 podcasts (audio only) Play this episode:Enhanced version
Audio only:
How does a tiny bacterium cause such rapid deaths? Cholera is a toxin-mediated disease. Vibrio cholerae produces cholera toxin, an enterotoxin which acts on the mucosal epithelium lining the small intestine, causing cell death and massive loss of body fluids into the gut, resulting in the the characteristic massive diarrhoea associated with the disease. Death is caused by hypovolemic shock due to the loss of body fluids, so first aid for cholera involves oral rehydration with isotonic liquids to combat these symptoms. Antibiotics are then given to speed up resolution of the infection.
Cholera seems to have originated in the Indian subcontinent and the disease spread by trade routes to Russia, then to Western Europe, and from Europe to North America during the nineteenth century. The history of cholera has been marked by a series of pandemics:
1816-1826 – First cholera pandemic
1829-1851 – Second cholera pandemic
1852-1860 – Third cholera pandemic. During this pandemic in 1854 John Snow identified contaminated water as the source of the disease by removal of the handle of the Broad Street pump in London.
1863-1875 – Fourth cholera pandemic
1881-1896 – Fifth cholera pandemic
1899-1923 – Sixth cholera pandemic
1961-1970s – Seventh cholera pandemic
Currently the disease is following a more endemic pattern, cropping up in poor countries and after natural disasters.
Vaccines against cholera are available but are not currently recommended for routine use. New oral vaccines against cholera are being developed, including a live-attenuated vaccine containing genetically manipulated V. cholerae, and an alternative vaccine containing killed whole-cell V. cholerae in combination with purified recombinant B subunit of the cholera toxin. Although the ultimate answer to cholera lies in public health and sanitation, at present the only feasible answer to cholera in poor countries is in vaccine development.
BBC News reports that Britain is running out of mycologists. There were 32 in the 1990s, but just eight now. Scientists say we should be worried as, without a British research base, other countries could stand to make lucrative fungi-based discoveries in everything from medicine to engineering.
Alternative methods to antimicrobial chemotherapy for combating infectious disease do exist. In this article in Microbiology Today, Roy Sleator describes the role of probiotics in keeping pathogens at bay:
