An international collaborative research effort involving scientists from the Wellcome Sanger Institute, the University of Toronto, the Institut Pasteur and Sana'a University has revealed the source of antibiotic resistance that emerged in bacteria driving the cholera outbreak that is currently affecting Yemen. The results of their research, published on September 28, 2023 in the journal Nature Microbiology, emphasise the importance of ongoing genomic surveillance of pathogens to monitor the emergence of multidrug-resistant strains.
The cholera outbreak in Yemen is the largest in modern history, responsible for more than 2.5 million cases and at least 4,000 deaths since 20161. Cholera is an epidemic infectious disease caused by cholera vibrios, a lineage of the bacterium Vibrio cholerae (V. cholerae) that produces cholera toxin2.
In its severe forms, the disease presents as intense diarrhoea and vomiting causing dehydration that can lead to death in just hours. While rehydration forms the basis of cholera treatment, antibiotics help shorten the disease’s duration, limiting the risk of complications for patients and the length of time they carry and shed V. cholerae. This reduces the potential for spread to others. Macrolides, a class of antibiotics, were widely used in Yemen until early 2019 to treat moderate to severe cases of cholera in pregnant women and children, who represented a significant number of cases.
However, starting in 2018, healthcare professionals observed a troubling trend: patients were no longer responding to these frontline antibiotic treatments.
In this new study, researchers from the Wellcome Sanger Institute, University of Toronto, Institut Pasteur, Sana'a University and their collaborators set out to uncover the reasons behind this growing drug resistance, analysing 260 V. cholerae DNA samples collected in Yemen between 2016 and 2019.
The team found that a type of V. cholerae containing multidrug-resistant genetic elements took over as the main pathogen during the Yemen outbreak period, likely from the widespread use of antibiotics at the time.
They identified the presence of a new plasmid — a small, circular DNA molecule — in all cholera vibrio samples isolated since November 2018. This plasmid, which exhibits a highly unusual degree of stability in V. cholerae3, introduced genes conferring resistance to multiple clinically used antibiotics, including macrolides.
The researchers also found the multidrug-resistant plasmid in other V. cholerae lineages of environmental origin which occasionally cause infections in humans but do not lead to cholera4. This finding suggests that V. cholerae may have acquired the antibiotic-resistant plasmid from these local strains. The strong selective pressure created by extensive antibiotic use at the time may have driven this process.
Dr Florent Lassalle, first author of the study at the Wellcome Sanger Institute, said: "This type of cholera pathogen was already highly successful before 2019, causing the largest cholera outbreak in recorded history. Now it has revealed how adaptable it is in the face of drug selection. What we have shown is the unexpectedly stable emergence of a new kind of cholera pathogen that combines the disease-causing tools of the one epidemic strain with the staying-power tools of others. This situation calls for more research into the evolution of bacterial genomes. With a better understanding of how V. cholerae evolves and its ability to drive disease outbreaks, we can improve strategies to fight it."
Professor François-Xavier Weill and Dr Marie-Laure Quilici, both senior authors of the study at the Institut Pasteur, Paris, said: "This cholera strain, which has also been found in the Southeast African region, has the ability to pick up plasmids carrying multidrug resistance. This unexpected behaviour poses a new threat for cholera control, and needs to be fully understood before we can develop effective mitigation strategies."In the meantime, regular and standardised surveillance of Vibrio cholerae strains' susceptibility to antibiotics is essential, so that rapid adjustments can be made to antibiotic therapy if a resistant strain emerges."
Dr Abdul-Elah Al-Harazi, senior author of the study and director of the National Centre of the Public Health Laboratories, Yemen, said: "The ongoing global spread of this resilient cholera strain is deeply concerning. Conducting this study was particularly challenging due to the ongoing conflict in Yemen. Nevertheless, this was a collaborative effort involving multiple institutions across various countries, aimed at uncovering the underlying causes of cholera. The ultimate measure of our study's success, beyond the critical observations we have collectively made, lies in making our collective expertise, processes, and knowledge accessible to those who need it most. This was demonstrated in our recent symposium, uniting those from all over the world to accelerate our response against infectious diseases. This remains our shared objective, one that requires even more concerted efforts to achieve. It is clear from our findings that without more accurate data, this pathogen is unlikely to be eradicated anytime soon. However, with better data, we can instigate fundamental changes that will significantly improve public health on the ground."
This research was supported by Wellcome and the Institut Pasteur. For full funding acknowledgements, please refer to the publication.
2. While V. cholerae bacteria are very diverse, the strains that caused the current cholera outbreak only belong to the 7th pandemic El-Tor (7PET) lineage, which emerged in 1961. Weill et al., Science (2017) ; https://doi.org/10.1126/science.aad5901
4. Scientists were able to determine gene exchange between strains belonging to non-7PET lineages (local strains) and the 7PET lineage (epidemic strain/Vibrio cholerae) as they both carry the same plasmid.
5. The collaborative consortium of authors, led by Dr Abdul-Elah Al-Harazi, Dr Marie-Laure Quilici, Professor François-Xavier Weill, Dr Ghulam Dhabaan and Professor Nicholas Thomson, organised an online symposium in October 2022 to showcase the various expertise of each group, and to foster collective thinking to take this initiative forward. Recordings of these talks can be accessed online at: https://sites.google.com/view/yemencholeragenome/home
These data sets are available for interactive analysis at: https://github.com/flass/yemenpaper ; https://github.com/flass/yemenpaper and https://figshare.com/projects/genomic_epidemiology_of_the_cholera_outbreak_in_Yemen_2018-2019/122507
Genomic epidemiology reveals multidrug resistant plasmid spread between Vibrio cholerae lineages in Yemen, Nature Microbiology, 28th September 2023
Florent Lassalle1, Salah Al-Shalali2, Mukhtar Al-Hakimi 2, Elisabeth Njamkepo 3, Ismail Mahat Bashir4, Matthew J. Dorman 1,5, Jean Rauzier3, Grace A. Blackwell1,6, Alyce Taylor-Brown 1, Mathew A. Beale 1, Adrián Cazares 1, Ali Abdullah Al-Somainy7, Anas Al-Mahbashi2, Khaled Almoayed7, Mohammed Aldawla8, Abdulelah Al-Harazi7, Marie-Laure Quilici 3,11, François-Xavier Weill 3,11, Ghulam Dhabaan 9,11 & Nicholas R. Thomson 1,10,11
1 Parasites and Microbes Programme, Wellcome Sanger Institute, Hinxton, UK.
2 Faculty of Science, Sana’a University, Sana’a, Yemen.
3 Institut Pasteur, Université Paris Cité, Unité des Bactéries pathogènes entériques, Paris, France.
4 WHO Yemen country office, Sana’a, Yemen.
5 Churchill College, Cambridge, UK.
6 EMBL-EBI, Hinxton, UK.
7 National Centre of Public Health Laboratories, Sana’a, Yemen.
8 Ministry of Public Health, Infection Control Unit, Sana’a, Yemen.
9 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
10 London School of Hygiene and Tropical Medicine, London, UK.
11 These authors jointly supervised this work: Marie-Laure Quilici, François-Xavier Weill, Ghulam Dhabaan, Nicholas R. Thomson.