Discovery of High-level Antibiotic Resistance Mechanisms in Nature.
Lead Research Organisation:
The Francis Crick Institute
Department Name: Research
Abstract
Pathogenic bacteria are rapidly evolving resistance to antibiotic treatment. This fact is one of the greatest challenges in modern medicine and agriculture. If this trend is not reversed in the next decades, is estimated that 10 million people a year will die from antibiotic resistant infections by 2050.
The methods that bacteria can use to avoid being killed by antibiotics are very diverse and many of them are still unknown. If we could have a comprehensive and detailed catalogue of the existing mechanisms of antibiotic resistance, we could (a) be better informed to choose the best antibiotic to treat an infection by a particular bacteria (b) find or design new drugs to counteract these resistance mechanisms, so that the "resistance neutralising" drug can then be prescribed together with the antibiotic. An example of this combination therapy is the antibiotic amoxicillin that is commonly given to patients with another drug called clavulanic acid. This is because resistant bacteria make a protein that breaks down the amoxicillin, but clavulanic acid inactivates this protein. The clavulanic acid-bound inactive bacterial protein, leaves the amoxicillin intact and therefore able to kill the bacteria.
In this project, we aim to discover and to understand a variety of mechanisms of antibiotic resistance in a group of bacteria known as the mycobacteria. This group includes a number of important human and animal pathogens, causing hard to treat diseases such as human and bovine tuberculosis, leprosy and Buruli ulcer, among others.
Upon completion we will have (i) tested the sensitivity/resistance of 48 different species of mycobacteria against 40 antibiotics currently in use in the clinic (ii) identified and characterised the mechanism(s) used by the bacteria to become resistant to these antibiotics. These mechanisms normally involve the production of proteins that can somehow render the antibiotic inactive, and we will find the proteins responsible and the mode of antibiotic inactivation.
We will focus our study on mycobacteria, but different groups of bacteria tend to share mechanisms of resistance. We therefore expect that our discoveries will also impact on the understanding and treatment of many other bacterial infections of humans and animals.
The methods that bacteria can use to avoid being killed by antibiotics are very diverse and many of them are still unknown. If we could have a comprehensive and detailed catalogue of the existing mechanisms of antibiotic resistance, we could (a) be better informed to choose the best antibiotic to treat an infection by a particular bacteria (b) find or design new drugs to counteract these resistance mechanisms, so that the "resistance neutralising" drug can then be prescribed together with the antibiotic. An example of this combination therapy is the antibiotic amoxicillin that is commonly given to patients with another drug called clavulanic acid. This is because resistant bacteria make a protein that breaks down the amoxicillin, but clavulanic acid inactivates this protein. The clavulanic acid-bound inactive bacterial protein, leaves the amoxicillin intact and therefore able to kill the bacteria.
In this project, we aim to discover and to understand a variety of mechanisms of antibiotic resistance in a group of bacteria known as the mycobacteria. This group includes a number of important human and animal pathogens, causing hard to treat diseases such as human and bovine tuberculosis, leprosy and Buruli ulcer, among others.
Upon completion we will have (i) tested the sensitivity/resistance of 48 different species of mycobacteria against 40 antibiotics currently in use in the clinic (ii) identified and characterised the mechanism(s) used by the bacteria to become resistant to these antibiotics. These mechanisms normally involve the production of proteins that can somehow render the antibiotic inactive, and we will find the proteins responsible and the mode of antibiotic inactivation.
We will focus our study on mycobacteria, but different groups of bacteria tend to share mechanisms of resistance. We therefore expect that our discoveries will also impact on the understanding and treatment of many other bacterial infections of humans and animals.
Technical Summary
The discovery of novel determinants and mechanisms of antibiotic resistance is crucial to human and animal health. In addition to an immediate impact, informing on treatment options, this knowledge can guide novel drug discovery programmes aimed at preventing resistance. In fact, this approach has been successfully used for decades to re-sensitise bacteria against antibiotics that are no longer efficacious. For example, beta-lactamase inhibitors are routinely prescribed in conjunction with beta-lactam antibiotics.
Our novel approach to discover unknown mechanisms of antibiotic resistance relies on a comparative analysis of a carefully selected subgroup of species representative of an entire bacterial genus, the mycobacteria. The Mycobacterium genus was chosen as: (i) it includes several important human pathogens (e.g. Mycobacterium tuberculosis, M. leprae, M. ulcerans and M. abscessus) and also animal pathogens of economic importance (e.g. M. bovis, M. avium, M. marinum); (ii) resistance to nearly all antimycobacterial agents available has been observed; and (iii) with the exception of the most important pathogenic species, there is scant information on the biology and pharmacology of most members of this genus.
Our project has three aims:
(1) Discovery of mycobacterial species that display high levels of antibiotic resistance, compared to other mycobacterial species.
(2) Discovery of candidate antibiotic metabolites, proteins and genes involved in the antibiotic resistance phenotypes observed in (1). This goal will be accomplished by a combination of microbiological, metabolomics, proteomics and genomics experiments, some of which have been pioneered by our group.
(3) Demonstration of which of the candidate metabolites, proteins and genes uncovered in (2) are the bona fide antibiotic resistance determinants. And elucidate the molecular and cellular mechanisms underpinning antibiotic resistance, employing a combination of microbiology and biochemistry.
Our novel approach to discover unknown mechanisms of antibiotic resistance relies on a comparative analysis of a carefully selected subgroup of species representative of an entire bacterial genus, the mycobacteria. The Mycobacterium genus was chosen as: (i) it includes several important human pathogens (e.g. Mycobacterium tuberculosis, M. leprae, M. ulcerans and M. abscessus) and also animal pathogens of economic importance (e.g. M. bovis, M. avium, M. marinum); (ii) resistance to nearly all antimycobacterial agents available has been observed; and (iii) with the exception of the most important pathogenic species, there is scant information on the biology and pharmacology of most members of this genus.
Our project has three aims:
(1) Discovery of mycobacterial species that display high levels of antibiotic resistance, compared to other mycobacterial species.
(2) Discovery of candidate antibiotic metabolites, proteins and genes involved in the antibiotic resistance phenotypes observed in (1). This goal will be accomplished by a combination of microbiological, metabolomics, proteomics and genomics experiments, some of which have been pioneered by our group.
(3) Demonstration of which of the candidate metabolites, proteins and genes uncovered in (2) are the bona fide antibiotic resistance determinants. And elucidate the molecular and cellular mechanisms underpinning antibiotic resistance, employing a combination of microbiology and biochemistry.