Periodic Reporting for period 3 - uCARE (Understanding Circumventing Antibiotic REsistance)
Reporting period: 2022-03-01 to 2023-08-31
Infections by bacteria resistant to most, if not all, available antibiotics are found in alarmingly increasing numbers world-wide. As a result, bacterial infections, once considered easily treatable, are becoming life-threatening again, and pose a serious threat to public health. The problem goes beyond infectious diseases and permeates most fields of modern medicine: e.g. invasive surgery, transplantation, chemotherapy, care of critically or chronically ill are all tightly linked to our ability to control infections. The potential socioeconomic impact of reaching a stage in which antibiotics do not work is tremendous, with costs of rising antimicrobial resistance (AMR) being estimated at the tens of trillion dollars over the next decades, and a clear risk for decrease in life expectancies and quality. Awareness for the seriousness of the situation has risen over the past years, and the first actions to mitigate some aspects of this complex problem are underway. However, more fundamental and applied research is urgently needed to find new strategies and sustainable solutions to avoid that AMR becomes the source for new epidemics or even a pandemic.
Development of resistance is an inherent problem of antibiotics, something that Fleming already pointed out in 1945 in his Nobel acceptance speech: their use not only inhibits the pathogenic agent, but also selects for resistance, undermining their long-term activity. The broad use of antibiotics in medicine but also in food industry over the past 70 years, together with the drought in new compound development over the last three decades, have provided the ideal settings for the rise and spread of resistance to most frontline antibiotics, even those of “last resort”. New effective antibacterial therapies are urgently needed, and effort is put towards this direction. Yet, discovery of new antibiotics is a long process with high attrition rates. More importantly, developing new compounds without understanding the paths and mechanisms that lead to antibiotic resistance selection and spreading, and finding ways to overcome them, is a Sisyphean effort. The overarching goals of this proposal are to improve our basic understanding of antibiotic resistance, assessing the role of a potentially strong and previously unappreciated source of selective pressure for resistance development, that of non-antibiotic drugs, and exploring ways of mitigating and reverting antibiotic resistance development using combinatorial therapies.
Since their discovery, antibiotics have been heavily used for prophylaxis. Their popularity is closely linked to their high efficacy and the high-gain/low-risk for the individual. Community risks, such as antibiotic resistance, were put in second line for decades, since the high pace of new compound development ensured we were several steps ahead in this race. However, as the antibiotic development tap started to run dry, the community risks of uncontrolled antibiotic usage became apparent, and nowadays large efforts to controlling antibiotic use are under way– e.g. antibiotic stewardship programs. Yet, is antibiotic consumption the only driving force for resistance?
We recently established that commonly used drugs against diseases unrelated to infection have also an impact on the human gut microbiota. Microbes that are more resistant to non-antibiotic drugs are also more resistant to antibiotics, due to partially common resistance mechanisms 3. This implies that by affecting the gut microbiota, many non-antibiotic drugs may be also selecting for resistance to antibiotics. As we use (non-antibiotic) pharmaceuticals frequently and often for longer periods, this raises the question of whether polypharmacy is a driver of antibiotic resistance in commensal and opportunistic pathogen gut microbes. Here, we want to explore this hypothesis by mapping the cross-resistance/sensitivity patterns between antibiotics and non-antibiotics, and elucidating the underlying antibacterial mode-of-action and resistance mechanisms of non-antibiotic drugs. This knowledge will allow us to mitigate or exploit the microbial side-effects of these drugs in a targeted manner, and opens new paths for rational design of drug combinations.
Although extensively used for other diseases, drug combinations have only had limited use for treating bacterial infections, mostly to increase spectrum coverage. The lack of new antibiotics has revived interest in them, especially since they can offer fast solutions in cases in which individual compounds are already approved for clinical use. We recently performed a large screen of drug pairwise combinations in bacteria, establishing that interactions are mainly species-specific and identifying many new synergies, some of which are equally potent against multi-drug resistant clinical isolates. In this grant we want to want use drug combinations to delay AMR development or revert existing resistance. To delay resistance one needs to minimize the selective pressure placed by the antibiotic, focus the target group that this pressure is applied to (narrow-spectrum therapies), or make it harder for the microbe to find survival strategies. To revert resistance, the resistance trait needs to be turned into fitness cost for the microbe.
The overall objectives of this project are to:
i. Understand the extent non-antibiotics drive AMR and the underlying mechanisms
ii. Elucidate the antimicrobial action of non-antibiotic drugs
iii. Identify ways to mitigate the microbial side-effects of non-antibiotic drugs, thus decreasing the selective pressure for AMR
iv. Use the antimicrobial side-effects of non-antibiotic drugs to revert AMR
v. Identify genetic elements that slow down AMR development and use knowledge to design new less-prone-to-AMR combination therapies
Development of resistance is an inherent problem of antibiotics, something that Fleming already pointed out in 1945 in his Nobel acceptance speech: their use not only inhibits the pathogenic agent, but also selects for resistance, undermining their long-term activity. The broad use of antibiotics in medicine but also in food industry over the past 70 years, together with the drought in new compound development over the last three decades, have provided the ideal settings for the rise and spread of resistance to most frontline antibiotics, even those of “last resort”. New effective antibacterial therapies are urgently needed, and effort is put towards this direction. Yet, discovery of new antibiotics is a long process with high attrition rates. More importantly, developing new compounds without understanding the paths and mechanisms that lead to antibiotic resistance selection and spreading, and finding ways to overcome them, is a Sisyphean effort. The overarching goals of this proposal are to improve our basic understanding of antibiotic resistance, assessing the role of a potentially strong and previously unappreciated source of selective pressure for resistance development, that of non-antibiotic drugs, and exploring ways of mitigating and reverting antibiotic resistance development using combinatorial therapies.
Since their discovery, antibiotics have been heavily used for prophylaxis. Their popularity is closely linked to their high efficacy and the high-gain/low-risk for the individual. Community risks, such as antibiotic resistance, were put in second line for decades, since the high pace of new compound development ensured we were several steps ahead in this race. However, as the antibiotic development tap started to run dry, the community risks of uncontrolled antibiotic usage became apparent, and nowadays large efforts to controlling antibiotic use are under way– e.g. antibiotic stewardship programs. Yet, is antibiotic consumption the only driving force for resistance?
We recently established that commonly used drugs against diseases unrelated to infection have also an impact on the human gut microbiota. Microbes that are more resistant to non-antibiotic drugs are also more resistant to antibiotics, due to partially common resistance mechanisms 3. This implies that by affecting the gut microbiota, many non-antibiotic drugs may be also selecting for resistance to antibiotics. As we use (non-antibiotic) pharmaceuticals frequently and often for longer periods, this raises the question of whether polypharmacy is a driver of antibiotic resistance in commensal and opportunistic pathogen gut microbes. Here, we want to explore this hypothesis by mapping the cross-resistance/sensitivity patterns between antibiotics and non-antibiotics, and elucidating the underlying antibacterial mode-of-action and resistance mechanisms of non-antibiotic drugs. This knowledge will allow us to mitigate or exploit the microbial side-effects of these drugs in a targeted manner, and opens new paths for rational design of drug combinations.
Although extensively used for other diseases, drug combinations have only had limited use for treating bacterial infections, mostly to increase spectrum coverage. The lack of new antibiotics has revived interest in them, especially since they can offer fast solutions in cases in which individual compounds are already approved for clinical use. We recently performed a large screen of drug pairwise combinations in bacteria, establishing that interactions are mainly species-specific and identifying many new synergies, some of which are equally potent against multi-drug resistant clinical isolates. In this grant we want to want use drug combinations to delay AMR development or revert existing resistance. To delay resistance one needs to minimize the selective pressure placed by the antibiotic, focus the target group that this pressure is applied to (narrow-spectrum therapies), or make it harder for the microbe to find survival strategies. To revert resistance, the resistance trait needs to be turned into fitness cost for the microbe.
The overall objectives of this project are to:
i. Understand the extent non-antibiotics drive AMR and the underlying mechanisms
ii. Elucidate the antimicrobial action of non-antibiotic drugs
iii. Identify ways to mitigate the microbial side-effects of non-antibiotic drugs, thus decreasing the selective pressure for AMR
iv. Use the antimicrobial side-effects of non-antibiotic drugs to revert AMR
v. Identify genetic elements that slow down AMR development and use knowledge to design new less-prone-to-AMR combination therapies
In the first half of the project period we have made significant progress in all main objectives.
We have developed a series of experimental and computational tools and approaches to systematically assess cross-resistance/sensitivity between drugs (antibiotic or non-antibiotics) in different microbes, pathogens or commensals, and to identify genetic elements that delay AMR development. We have also introduced new quantitative technologies (thermal proteome profiling) in different gut microbial species, which have enabled us to identify the antibacterial mode of action of some non-antibiotic drugs.
We have also provided a proof-of-principle of how drug combinations can be used to narrow the spectrum of antibiotics and mitigate their collateral damage to commensal species of the gut microbiota. The second drug is used as an antidote towards the collateral damage of the antibiotic, and at the same time decreases the chance for AMR development, as microbial population size that selective pressure is applied to is smaller. The antidote function works in different microbiome communities and in animal experiments (Maier et al. Nature 2021).
We have developed a series of experimental and computational tools and approaches to systematically assess cross-resistance/sensitivity between drugs (antibiotic or non-antibiotics) in different microbes, pathogens or commensals, and to identify genetic elements that delay AMR development. We have also introduced new quantitative technologies (thermal proteome profiling) in different gut microbial species, which have enabled us to identify the antibacterial mode of action of some non-antibiotic drugs.
We have also provided a proof-of-principle of how drug combinations can be used to narrow the spectrum of antibiotics and mitigate their collateral damage to commensal species of the gut microbiota. The second drug is used as an antidote towards the collateral damage of the antibiotic, and at the same time decreases the chance for AMR development, as microbial population size that selective pressure is applied to is smaller. The antidote function works in different microbiome communities and in animal experiments (Maier et al. Nature 2021).
We expect to conclude the major objectives of this grant and provide fundamental mechanistic knowledge on how non-antibiotic drugs inhibit microbes and how microbes resist to both antibiotics and non-antibiotic drugs, but also proof–of–principle applications of how this knowledge can be used to prevent, delay or even revert AMR development.