Using existing drugs to make bacteria susceptible to antibiotics

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The Microbiology Society is undertaking a project entitled A Sustainable Future as part of our 75th Anniversary, which aims to highlight the Sustainable Development Goals (SDGs) to our members and empower them to use their research to evidence and impact the goals. Earlier this year, we put a call out to our members to submit case studies in the following three areas: antimicrobial resistance, soil health and the circular economy.

This case study is written by Dr Michelle M.C. Buckner, who is a lecturer at the University of Birmingham and a member of the Microbiology Society. It focuses on antimicrobial resistance; a naturally occurring process, whereby micro-organisms (bacteria, viruses, fungi and parasites) can change and adapt over time, either by modifying the target of the antimicrobial, or by developing and exchanging resistance genes.

Introduction to the project

Globally, antimicrobial resistant (AMR) bacterial infections are increasing, leaving limited treatment options. An important characteristic of bacteria is their ability to share genetic information, including AMR genes, via mobile genetic elements such as plasmids. Plasmids are usually circular pieces of DNA which replicate separately from the chromosome. They may contain multiple resistance genes, such as carbapenemases which give resistance to carbapenem drugs, and extended spectrum beta-lactamases (ESBLs) which give resistance to third generation cephalosporins. Gram-negative Enterobacteriaceae such as Escherichia coli and Klebsiella pneumoniae producing ESBLs and carbapenemases are classified as critical priorities by the World Health Organization (WHO) for new drug development.1

Transmission of plasmids between bacteria, predominantly occurs through a process called conjugation, whereby plasmids move along a bridge-like structure into new bacteria. Once in a new microbial host, plasmids can become stable in the population through a variety of mechanisms including co-evolution,2 and can persist even in the absence of antibiotics.3,4 Bacterial sequencing efforts have identified AMR plasmids around the world in a variety of environments, in particular in the gastrointestinal (GI) tract, where for example they can be acquired after travel to countries with high AMR levels.5–7 Infections caused by bacteria with AMR plasmids are responsible for some of the most difficult to treat and often multi-drug resistant infections.

What are the challenges/needs that this research/initiative addresses?

Bacteria carry and can transmit AMR plasmids to other bacteria. Together, carriage and transmission of AMR plasmids can lead to an increased incidence of infections with resistant bacteria.

Can we develop methods to either remove AMR plasmids or AMR genes from bacteria? Or can we develop methods to stop AMR plasmids/genes from spreading between bacteria?

What findings and solutions were provided by this research/initiative?

Driven by rising rates of AMR, over the past 10 years research in this area has begun to increase. Different groups are studying different methods which could be used to remove AMR or prevent spread of AMR plasmids/genes. We have been looking at drug repurposing as a source for compounds to either remove AMR plasmids from bacteria and/or prevent the AMR plasmids from spreading.8 We have used a fluorescent system to monitor two AMR plasmids which originally carried an ESBL gene in uropathogenic E. coli, or a carbapenemase gene in K. pneumoniae. Using this system, we monitored the impact of FDA-approved drugs on AMR plasmid transmission and persistence. We found azidothymidine (AZT), used to treat HIV, was able to reduce the prevalence of both plasmids in their respective bacterial strain.

How can this research/initiative support the transition to a more sustainable future?

My team is aiming to develop drugs that can be used to reduce the prevalence of AMR genes in targeted and high-risk settings. These could include, for example, a care home with an outbreak of carbapenem resistant organisms, or for a patient returning after medical procedures in a country with high levels of AMR. The use of existing drugs to maintain antibiotic susceptibility improves sustainability in a few key ways. In addition to human medicine, the drugs and compounds that we develop could be used in targeted veterinary settings, potentially improving the health of animals, which could improve sustainability of agriculture. Drug re-purposing allows the use of existing information and data, such as safety profiles, side effects and pharmacokinetics, which streamlines to translation process and improves research sustainability. Finally, and most importantly, by making bacteria susceptible to existing antibiotics, our research aims to prolong the life of these crucial existing medicines and to help reduce the emergence of resistance to new antibiotics.

References

1.            Tacconelli, E. et al. Discovery, research, and development of new antibiotics: the WHO priority list of antibiotic-resistant bacteria and tuberculosis. Lancet Infect. Dis. 18, 318–327 (2018).

2.            San Millan, A. et al. Positive selection and compensatory adaptation interact to stabilize non-transmissible plasmids. Nat. Commun. 5, 5208 (2014).

3.            Buckner, M. M. C. et al. Clinically Relevant Plasmid-Host Interactions Indicate that Transcriptional and Not Genomic Modifications Ameliorate Fitness Costs of Klebsiella pneumoniae Carbapenemase-Carrying Plasmids. mBio 9, e02303-17 (2018).

4.            Lopatkin, A. J. et al. Persistence and reversal of plasmid-mediated antibiotic resistance. Nat. Commun. 8, 1689 (2017).

5.            Arcilla, M. S. et al. Import and spread of extended-spectrum β-lactamase-producing Enterobacteriaceae by international travellers (COMBAT study): a prospective, multicentre cohort study. Lancet Infect. Dis. 17, 78–85 (2017).

6.            Vading, M. et al. Frequent acquisition of low-virulence strains of ESBL-producing Escherichia coli in travellers. J. Antimicrob. Chemother. 71, 3548–3555 (2016).

7.            Bevan, E. R., McNally, A., Thomas, C. M., Piddock, L. J. V & Hawkey, P. M. Acquisition and Loss of CTX-M-Producing and Non-Producing Escherichia coli in the Fecal Microbiome of Travelers to South Asia. mBio 9, e02408-18 (2018).

8.            Buckner, M. M. C. et al. HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes. mBio 11, (2020).


© Michelle Buckner
About the author

Dr Michelle M.C. Buckner is a lecturer at the University of Birmingham and a member of the Microbiology Society. More information about her work is available here.