When bacteria, viruses, fungi and parasites no longer respond to medicines: this is set to become one of the major health threats of the 21st century. Francesco Imperi, Associate Professor of Microbiology at Roma Tre University (Italy), is working on novel strategies to tackle this antimicrobial resistance (AMR), more specifically in multidrug resistant bacterial human pathogens.
We interview him ahead of the event that aims to raise awareness about this topic organised by the European Parliament’s Panel for the Future of Science and Technology (STOA) on 29 March 2023.
Why are we seeing the emergence of bacteria that are resistant to antibiotics?
Francesco Imperi: We are seeing the emergence of antibiotic-resistant bacteria because we are using antibiotics. Antibiotics kill or inhibit the growth of bacteria, but bacteria evolve very fast so they can easily mutate or acquire resistance genes. Antibiotics end up selecting for these resistant bacteria. The more we use antibiotics, the more probable is the emergence and spread of antibiotic-resistant bacteria.
We are not always using antibiotics properly, for example by using them in patients who are infected with viruses rather than bacteria or to prevent infections in livestock. We should avoid the use of antibiotics when they are not needed.
How concerned should we be? Is drug resistance easily transferable?
Francesco Imperi: Because bacteria divide and evolve very fast in a bacterial population with billions of cells, it is very easy for one of them to become resistant. Once a cell has a gene that confers resistance, it can easily be transferred to other bacteria through pieces of DNA called mobile genetic elements. Mobile genetic elements often contain many drug resistance genes, so when a bacterium acquires one of these elements it automatically acquires resistance to a number of antibiotics. This can result in what is referred to as multidrug resistant bacteria that cannot be treated with most of the antibiotics we are currently using.
What strategies are being pursued to tackle AMR?
Francesco Imperi: The first approach to tackle AMR is to prevent the spread of resistant bacteria and improve antibiotic stewardship programmes. We need to study the prevalence and distribution of antibiotic-resistant bacteria and try to use only those antibiotics that are likely to work against them.
Another approach is to develop new antibiotics and save them to avoid bacteria becoming resistant to them. Even if a very good new antimicrobial is found, it should only be used in patients that don’t respond to the available drugs. Investing in the development of a drug that won’t be sold is not an attractive proposition for companies, government funding is required as an incentive.
The third strategy is to improve the antibiotics we already have. There are many ways to do this.
Adjuvants for example are molecules that don’t have antimicrobial activity themselves but can boost the activity or prolong the lifespan of antibiotics. Some adjuvants, referred to as ‘resistance breakers’, work by targeting the mechanisms that make bacteria resistant, so they revert to being sensitive to the antibiotic. Some resistance breakers are already in clinical use. For instance combining beta-lactam antibiotics with an inhibitor of the bacterial enzymes beta-lactamases that degrade them, increases the efficacy of treatment.
Other adjuvants that are in development work by making the bacterial envelope more permeable to the antibiotic or by blocking the activity of efflux pumps that pump antibiotics out from bacterial cells. Because efflux pumps are involved in multidrug resistance, this approach could reverse resistance to many antibiotics.
Bacteriophages, viruses that specifically target and kill bacteria, have also been used successfully to treat infections caused by multidrug resistant bacteria on a compassionate basis. However, they face the same problem as antibiotics: bacteria can evolve to develop resistance to phage infections. Phage therapy requires identifying the right bacteriophage to target the infection being treated, which at present is labour intensive.
Finally, a lot of research is being carried out on antivirulence drugs that don’t kill bacteria but rather target mechanisms that are essential for pathogenesis. Thus, they stop bacteria from damaging the host and give the host’s immune system a better opportunity to fight the infection. Antivirulence compounds have shown promising effects in preclinical models but have not entered clinical trials, with the only exception of antibodies that neutralize or inactivate specific bacterial toxins. The use of antivirulence drugs is likely to be limited as they are generally specific for particular pathogens. Also, because antivirulence drugs don’t eradicate the infection their use will be restricted to immunocompetent patients, capable of producing a normal immune response. Immunocompromised patients are likely to require both antivirulence drugs and antibiotics.
In the case of gram-negative bacteria, which are intrinsically resistant to antibiotics because of their additional outer membrane, the delivery of antibiotics can be improved by linking them to siderophores, iron-binding molecules that are actively imported into bacterial cells. This so-called Trojan horse approach effectively smuggles the antibiotic into bacteria and has been used to treat adults with serious gram-negative bacterial infections.
Given the time and cost involved in developing new drugs, how optimistic can we be about tackling AMR globally?
Francesco Imperi: Antibiotics are still working and although there is an increase in the prevalence of antibiotic-resistant bacteria, we know we can reverse this trend. Many antibiotic resistance mechanisms bear a significant cost in terms of fitness. When this happens, antibiotic-resistant bacteria tend to grow a lot slower than antibiotic-sensitive ones. When the drug is removed the resistance often disappears as the sensitive bacteria grow better. If we can identify drug resistant bacteria and use the appropriate antibiotic against them, we can save our antibiotics and use them in the future.
It is important to develop new antibiotics even though they should not be used. Governments need to fund this, since there will be no financial reward from sales. They should also consider changing the way new antibiotics are evaluated. At present new antibiotics need to show higher or equal efficacy to antibiotics that are already on the market, yet given the inevitable emergence of resistance, even those that are not as active as existing ones could still be useful in the future, especially if they have a new mechanism of action that has not been exploited before.
Among the many strategies being pursued to tackle AMR, phage therapy is perhaps one we should focus on. Phages, or in full bacteriophages, are viruses that selectively target bacteria and kill them. Many clinical trials of phage therapy are currently underway. By combining two or more phage types to produce ‘phage cocktails’ it may be possible to overcome the limitation of phage specificity and achieve a broader spectra of activity. Adjuvants have already been shown to be effective and there are likely to be many more to discover and develop.
Would you say that infection prevention and investment into diagnostics and monitoring are more effective tools than the development of new drugs?
Francesco Imperi: We need both. Investing in preventive measures and monitoring tools is as important as investing in new drug development. The former will have effects straight away, whereas developing new antibiotics takes years so we must start now in order to have these drugs in the future and avoid a ‘post-antibiotics’ era in which antibiotic drugs no longer work at all.
Developing new diagnostics will help physicians identify antibiotic-resistant bacteria and discriminate between bacterial infections and viral ones on which antibiotics don’t have any effect, and thus, reduce inappropriate use of antibiotics.
