In 1928, Alexander Flemming discovered the bacteria killing compound, penicillin. Today this is just one of many antibiotics that provide what were once seen as almost miraculous cures to bacterial infection. However, we are once again facing the threats from the microscopic world because we are running out of effective antibiotics.
The excessive use of antibiotics over the last century has provided an evolutionary drive for bacteria to develop resistance to antibiotics and become fitter and potentially more deadly in some cases. Just as Fleming had warned in his 1945 Nobel Prize lecture about penicillin, every new class of antibiotic has been followed by bacteria becoming resistant to them. For the first 40 years of the antibiotic era, the fall of one antibiotic was followed by the discovery and rise of another. However, new antibiotics have become scarcer as pharmaceutical companies have realised their poor economic value in the long run. The last entirely new class of antibiotics to reach the market was discovered nearly 30 years ago.
The consequences of growing antimicrobial resistance extend beyond the human health sector. If the number of hard-to-treat infections continues to grow, not only will it become increasingly difficult to control infection in routine medical care, but it will be more difficult to maintain animal health and protect animal welfare, potentially impacting food supply.
Worldwide, various policy initiatives have been announced to deal with this problem. Here in the UK, the Review on Antimicrobial Resistance (AMR) was announced in July 2014 and will report ways to revitalise the research and development pipeline to produce new licensed antibiotics.
Coordinated global action is essential to reduce infection, keep drugs working, tackle the misuse of antimicrobials and develop alternatives. The UK set a five year (2013-2018) Antimicrobial Resistance strategy that mainly aims to slow the development and spread of antimicrobial resistance by focusing activities around these strategic aims:
conserve and steward the effectiveness of existing treatments
stimulate the development of new antibiotics
stimulate the development of new diagnostics and novel therapies
Animal Research Information will update this page with the results of this strategy and other initiatives and research with animals into new antibiotics as they become public.
Improve the knowledge and understanding of antimicrobial resistance
This is done through better intelligence archived in part by developing more effective early warning systems of emerging resistance.
A substantial and extended research effort will be needed to strengthen the UK’s modelling and forecasting capability. There needs to be a better understanding of the relative contributions of the inter-related factors that support the emergence and spread of resistance. Developing the evidence base will inform decisions that help make greater progress in addressing resistance.
The Wellcome Trust recently commissioned research into people’s relationship with antibiotics. They aimed to get a deep understanding of how people think and feel about antibiotics, their current understanding of the issue and the language they use around this area. It turns out most people think they know when they need antibiotics – and don’t need a doctor to tell them – and it is nearly always the severity rather than the type of illness that drives that thought. There is a strong sense of ‘validation’ of disease connected to antibiotics. However, most people are unaware of antibiotic resistance, let alone know how the misuse of antibiotic could lead to greater numbers of antibiotic resistant bacteria.
The welcome Trust believe doctors are key to changing the opinion and conduct of the public –a need for a behaviour change programme for doctors which provides clear guidelines and targets around when to prescribe antibiotics, and advice on how to manage patients.
The prevention, management and control of infection also needs to be included in undergraduate and postgraduate curricula for human medicine, nursing, and other medical professional training. Raising awareness about antibiotic resistance and its consequences, responsible prescribing, dispensing and administration are all crucial aspects of controlling the rise in antibiotic resistance.
A new study has already discovered how these drug-resistant bacterial cells maintain a defensive barrier, and if further research can find a way to bring down these walls - rather than targeting the bacteria directly - the bacteria could be prevented from developing drug resistance in the first place. The key to the discovery was a sophisticated piece of scientific equipment called the Diamond Light Source, which is capable of emitting intense beams of light to examine bacteria at an atomic level. With it, scientists examined the membranes of Gram-negative bacteria. Building on previous work where they managed to identify a specific weakness in the cell barrier, they uncovered how the wall is built and maintained - a crucial step forward in working out how to eventually crack it.
Conserve and steward the effectiveness of existing treatments
This is done by improving infection prevention and control and development of resources to facilitate optimal use of antibiotics in both humans and animals. The new UK strategies commit to an integrated approach to tackle antibiotic resistance as part of the ‘One-Health’ approach at national and international levels. This new ‘One health’ concept aims at strengthening the links between human health, animal health and management of the environment in order to protect public health through the control of pathogens in animals at the interface of men/animals/the environment.
The good news is that with the availability of multiple types of antibiotics, we may have an opportunity to selectively withdraw certain drugs – or at least to reduce their use by managing the simultaneous use of multiple types of drugs. The more types of drugs that are available, the more easily this can be done. In both academic and pharmaceutical-industry research planning this simple fact should serve to underscore the critical need for continual development and discovery of new drug classes.
It is key that infection prevention and control practices in human and animal health be improved, both through enhanced dissemination and implementation of best practice and better use of data and diagnostics. Prescribing practice need to by optimised through implementation of antimicrobial stewardship programmes that promote rational prescribing and better use of existing and new rapid diagnostics. Professional education, training and public engagement need to be enhanced to improve clinical practice and promote wider understanding of the need for more sustainable use of antibiotics.
These ‘Resistance management’ strategies have been gaining popularity over the years, and if executed correctly they might help turn the tables in our battle against drug resistance. But all of these strategies rely on the simple biological assumption that if a certain drug is prescribed infrequently, drug-resistant strains will be outcompeted, and resistance to that drug should fade.
Stimulate the development of new antibiotics
The discovery and development of new drugs takes time (about 10 to 15 years) and the efforts to develop new antibiotics are not keeping pace with the growth in microbial resistance. Another barrier to developing new antibiotics is their relatively low commercial return on investment, relative to investments in other therapeutic areas. This is because it is difficult to find new agents but also because there is a risk of inadequate return on investment given that duration of drug use is limited compared to drugs for chronic conditions. There are also concerns over the cost and complexity of the regulatory approval process and uncertainty about the regulatory environment for new antimicrobials.
Approaches to overcome market failure and to facilitate the regulatory pathways for new antibiotics and to provide new incentives for research and development are reported in the academic literature.
Work to reform and harmonise regulatory regimes relating to the licensing and approval of antibiotics, especially clinical trial requirements, is needed. The EU law that concerns the assessment and authorisation of new veterinary medicines is currently under revision. Regulatory uncertainty is another factor dissuading pharmaceutical companies from developing new antimicrobial products for veterinary use.
Stimulate the development of new diagnostics and novel therapies
Equally important is the research and development of novel approaches to the treatment and prevention of infections. Whilst it is essential that we should do all we can to conserve the effectiveness of existing antimicrobials, it is also important to ensure that we have effective treatments available for the future - not only new antibiotics but also vaccines and other therapeutic approaches for humans and animals.
This includes using substances to strengthen the immune response to bacterial infection, such as pre and probiotics. Naturally occurring bacteriophages, their enzymes and vaccines are already under consideration. Human and veterinary rapid diagnostics are urgently needed to help differentiate between bacterial and viral infections, as well as to enable fast identification of highly-resistant strains.
To maximise progress in this area it will be important for industry and academia to work together on an international level to accelerate discovery and development through well regulated research. This could allow better access to and use of surveillance data in human and animal sectors. Antimicrobial resistance research needs to be better identified and prioritised to focus activity and better understand the real issues of the subject.
The implementation of new immunisation programmes are highly recommended by the Joint Committee on Vaccination and Immunisation (JCVI). Improving vaccination coverage and promoting development of new vaccines including vaccines against multi-drug resistant organisms could help lower the general risk of infection, including risks from resistant strains.
See examples of alternatives to antibiotics
Engineered particles produce deadly toxin to bacteria
Researcher have engineered particles called “phagemids” capable of producing toxins that are deadly to targeted bacteria. Bacteriophages — viruses that infect and kill bacteria — have been used for many years to treat infection in some countries. Unlike traditional broad-spectrum antibiotics, these viruses target specific bacteria without harming the body’s normal microflora but can also potentially have harmful side effects. Indeed, they kill the bacteria by lysing the cell or causing it to burst which can lead to the release of pyrogenic toxins.
The researchers have engineered bacteriophages to express proteins that did not actually burst the cells, but instead increased the effectiveness of antibiotics when delivered at the same time. Alternatively, the phagemids infect specific bacteria with small DNA molecules known as plasmids that express different proteins or peptides that are toxic to the bacteria. The toxins are delivered directly into the bacteria. Researchers did not witness signs of significant resistance to the particles as this technique affects fundamental processes.
Bacteria eating viruses
Scientists are taking a fresh look at bacteria-killing viruses first isolated a century ago – bacteriophages. These attack bacteria but leave human cells unscathed, are still used in Russia, Georgia and Poland, but came out of use in the West with the mass production of penicillin. Phage therapy was never been tested in the clinic to the rigorous standards of Western medicine, as doctors opted for tried and tested antibiotics. But drug-resistant superbugs are making scientists rethink.
Phages kill bacteria by getting into bacterial cells and replicating - but the lack of hard data means their effectiveness and safety as a treatment is unclear.
Of all the alternatives to antibiotics, phages — viruses that attack bacteria — have been used the longest in the clinic. Scientists in the Soviet Union began developing phage therapies in the 1920s, and former Soviet countries continue the tradition. They work by attaching to bacteria as a host, injecting their DNA—which replicates—and causing the bacterial cell to burst open.
Phages have several advantages over antibiotics. Each type attacks only one type of bacterium, so treatments leave harmless (or beneficial) bacteria unscathed. And because phages are abundant in nature, researchers have ready replacements for any therapeutic strain that bacteria evolve to resist. The US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, now lists phages as a research priority for addressing the antibiotic crisis.
Bacteria cause infection, but some can also fight it by preying on fellow microbes. Several researchers are beginning to test these predatory bacteria in animal models and cell cultures.
The best-known species, Bdellovibrio bacteriovorus, is found in soil. It attacks prey bacteria by embedding itself between the host’s inner and outer cell membranes, and begins to grow filaments and replicate. Researchers are also studying the therapeutic potential of the predatory bacterium Micavibrio aeruginosavorus. And a team has engineered the gut bacterium Escherichia coli to produce peptides that kill Pseudomonas aeruginosa, a microbe that causes pneumonia.
Plants, animals and fungi have vastly different immune systems, but all make peptides — small proteins — that destroy bacteria. Peptides from creatures such as amphibians and reptiles, which are unusually resistant to infection, could yield new therapeutics.
Peptides with antibacterial activity have been isolated from frogs, alligators and cobras, among others, and some seem to be effective in epithelial cell cultures and at healing wounds in mice. These peptides can be modified to increase their potency, and several are in clinical trials. But synthesizing such molecules can be expensive, a hurdle that pharma industries must overcome to bring new peptide drugs to market.
PPMOs: peptide-conjugated phosphorodiamidate morpholino oligomer
PPMOs are lab synthesized forms of DNA or RNA that can silence specific genetic targets. According to researchers and animal studies, they function better than a standard antibiotic without the risk of bacteria becoming resistant to them. Unlike antibiotics, which attack a bacteria cell’s function and can cause other side effects, PPMOs disrupt the bacteria’s genes. Toxicity needs to be assessed in further testing before PPMOs can be used in humans.
Artificial bait for bacterial toxins
Engineered artificial nanoparticles made of lipids, "liposomes" that closely resemble the membrane of host cells act as decoys for bacterial toxins and so are able to sequester and neutralize them. Without toxins, the bacteria are rendered defenceless and can be eliminated by the cells of the host's own immune system.
In clinical medicine, liposomes are used to deliver specific medication into the body of patients. Here, the liposomes act as bait and attract bacterial toxins and so protect host cells from a dangerous toxin attack. Since the bacteria are not targeted directly, the liposomes do not promote the development of bacterial resistance. Mice which were treated with liposomes after experimental, normally fatal septicaemia survived without additional antibiotic therapy.
Interleukin 10 (IL-10) is a protein that is a kind of “off switch” for the immune system that can be manipulated by some bacteria and other pathogens to shut down an animal’s resistance before the microbes invade. Researchers have discovered how to disable IL-10 inside the intestine, the spot where many infections originate.
When an antibody to Interleukin-10 is fed to poultry, sheep and cattle, it blocks a variety of infections. The antibody turns the switch on allowing the immune system to kill the microbe. The researchers vaccinated laying hens to create antibodies to IL-10 and the immunity was successfully passed into the eggs.
CRISPR, a gene-editing technique is based on a strategy that many bacteria use to protect themselves against phages. Researchers are turning that system back on itself to make bacteria kill themselves.
Normally, the bacteria detect and destroy invaders such as phages by generating a short RNA sequence that matches a specific genetic sequence in the foreign body. This RNA snippet guides an enzyme called Cas9 to kill the invader by cutting its DNA. Scientists are now designing CRISPR sequences that target genomes of specific bacteria, and some are aiming their CRISPR kill switches at the bacterial genes that confer antibiotic resistance.
Metals such as copper and silver are the oldest antimicrobials. They were favoured by Hippocrates in the fourth century BC as a treatment for wounds, and were used even earlier by ancient Persian kings to disinfect food and water. Only now are researchers beginning to understand how metals kill bacteria.
Some groups are exploring the use of metal nanoparticles as antimicrobial treatments, although little research has been done in people. Because metals accumulate in the body and can be highly toxic, their use may be restricted mostly to topical ointments for skin infections.
An exception is gallium, which is toxic to bacteria that mistake it for iron, but is safe enough in people to be tested as an intravenous treatment for lung infections. This summer (2015), researchers at the University of Washington in Seattle will begin a phase II clinical trial of gallium in 120 patients with cystic fibrosis. Pilot studies found that the metal was moderately successful at breaking down microbial biofilms in the lungs and improving patients’ breathing.
Disarming bacterial toxins
Researcher successfully defeated a dangerous intestinal pathogen, Clostridium difficile, with a drug targeting its toxins rather than its life. They used what could be a good alternative to antibiotics. The study in mice constitutes the first-ever demonstration of a small molecule's ability to disarm C. difficile without incurring the collateral damage caused by antibiotics. Unlike antibiotics the drug didn't kill the bacteria, instead, it disabled a toxin it produces, preventing intestinal damage and inflammation and allowing the gut to be repopulated by healthy bacteria. The drug used has already been tested in clinical trials to treat other, unrelated conditions. So the researchers believe it could be moved rapidly into human trials for the treatment of C. difficile.
Theoretical mathematical model
Researchers have developed a novel mathematical method inspired by Darwinian evolution to use current antibiotics to eliminate or reduce the development of antibiotic-resistant bacteria. They showed that the ability of the bacterium E. coli to survive in antibiotics could be either promoted or hindered depending on the sequence of antibiotics given. They discovered that approximately 70 percent of different sequences of 2 to 4 antibiotics lead to resistance to the final drug.
Precision drug therapy - antibody-antibiotic conjugate
A precision drug therapy that wipes out bugs that hide in the body could help clear up persistent infections that do not respond to standard antibiotics. The treatment works by tagging antibiotics onto antibodies which home in on pathogens and deliver a lethal dose of drug directly to the heart of the infected tissues. The strategy could transform the treatment of patients with recurring bacterial infections, such as the hospital superbug MRSA, which can be extremely hard to treat even with powerful antibiotics. The approach also raises hopes for treating relapses in tuberculosis patients, and chronic infections that can take hold after heart surgery. Injections of the antibody-drug combination into infected mice wiped out Staphylococcus aureus infections far more effectively than antibiotics alone. The strategy could slow the emergence of antibiotic resistance because only the targeted bacteria are exposed to the drug, and reduce the harm that antibiotics inflict on healthy microbes that live in the gut.
zinc chelator upsets bacterial balance
Scientists have identified new agents that can be used in the fight against bacteria. Their approach is to use a molecule – a zinc chelator – that selectively binds the metal zinc and upsets the zinc balance in bacteria. Beta-lactam-type antibiotics such as penicillin have increasingly become ineffective because an enzyme in the bacteria – beta-lactamase – destroys the antimicrobial activity of the antibiotic. The zinc chelators upsets a sub-group of lactamases that depend on zinc, thus rendering the enzymes unable to harm the effect of the antibiotic.
Vaccines could be an important weapon in the fight against drug-resistant microbes. By using vaccines against bacterial infections, you prevent the diseases from occurring, thus eliminating the need for antibiotic treatment all together. If every child was vaccinated, the number of days when children under 5 are taking antibiotics against, for example, Streptococcus pneumoniae, the source of meningitis and pneumonia, would be cut by 47%. Such a drastic reduction could, in theory, make drug-resistant strains much less likely to evolve.
See why antibiotic resistance is also an important issue for pets and animals