Link between antidepressants and antibiotic resistance under microscope

Antibiotic resistance is increasing at an alarming rate, causing global concern. University of Otago researchers have secured funding to find out if a commonly prescribed medicine is adding to the problem.

The project, led by Dr Sam Wardell, Postdoctoral Fellow in the Department of Microbiology and Immunology, will investigate the role of antidepressants in promoting antibiotic resistance.

It is one of 13 Otago projects which received a total of $3.7 million in the latest Health Research Council’s funding rounds: Emerging Researcher, Pacific Health Research Emerging Leader Fellowship, and Explorer Grants.

Dr Wardell says antibiotic resistance is an international issue, and is getting worse.

“If we can understand the why, then we can start to develop new ways to treat resistant bacteria, or develop ways to prevent resistance arising in the first place.

“Up until recently it was thought antibiotic resistance only arose due to antibiotic exposure. Although this still happens, recent studies have shown non-antibiotic medicines can also cause antibiotic resistance,” he says.

His project, which secured a nearly $400,000 grant, will build on international research which found antidepressants caused antibiotic resistance in E.coli in a laboratory setting.

“This immediately caught my attention because I had never even considered that things as widely used as antidepressants could have an effect like this. This work will expand into other pathogenic bacteria, seeing if this also happens within animals, and even in humans.”

Dr Wardell is “incredibly grateful” to HRC for the funding.

“This project is the most personal I have ever designed. As someone who has had struggles with mental health issues and uses antidepressants, and who has had close friends lose their battles with mental health issues – whatever I can do to further understand how we can better help these people, I am excited to try.”

He hopes by opening discourse around antidepressants, their use will become less stigmatised.

“Unfortunately, there is still a societal stigma around antidepressants and mental health issues within Aotearoa. What’s even worse is that Māori are even less likely to be prescribed antidepressants and receive mental health treatment compared to others.

“You might think that showing that antidepressants can cause antibiotic resistance would lead to more of a stigma, I believe the opposite.

“Even more importantly, if antidepressants do cause antibiotic resistance within individuals prescribed them, by understanding why this happens and the mechanisms of how resistance progresses, we can actually inform treatments which might be more effective for these individuals should they get an infection in the future which requires antibiotics.”

Deputy-Vice-Chancellor (Research and Enterprise) Professor Richard Blaikie is very pleased with the continued support Otago receives from the HRC, and congratulates recipients on their success.

“We undertake important health research across a wide variety of fields, and it is particularly heartening to see early-career staff demonstrating leadership and receiving recognition in these rounds.

“It is also fantastic to see a strong suite of new innovative projects receive Explorer Grants. In both cases we can see that the future health research needs of Aotearoa is in good hands.”

Dr Helen Waddell
Department of Physiology
$335,631
Atrial fibrillation: linking heart cell structure to electrical function

Atrial fibrillation (AF) is the most common heart rhythm disorder in Aotearoa. Patients with AF experience a chaotic spread of electrical signals throughout the top of the heart, resulting in uncoordinated pumping of blood. This increases the risk of stroke, heart failure, and premature death. Therefore, a better understanding of AF is required. The current project will investigate how changes in cell-to-cell gateways between heart cells may cause disruption in the spread of electrical signals. It will utilise small human heart samples from patients with and without AF to perform high-resolution microscopy and live electrical mapping techniques. This project will also develop an experimental model of AF using human heart samples by rapid electrical stimulation. The model will screen the anti-arrhythmic drug flecainide (used clinically) and provide new information about its therapeutic action. This will provide key mechanistic insights that could aid the development of future AF therapies.

Dr Aline Boer
Department of Physiology
$400,000
Hypothalamic inhibition of GIPR signalling to increase health during ageing

The population in New Zealand and worldwide is ageing. Ageing is associated with an increased risk of health problems, including the development of type 2 diabetes, obesity, heart disease, and a decline in memory function. This research will investigate the hormone glucose-dependent insulinotropic polypeptide (GIP) and its potential to influence ageing and ageing-related health problems. We will use a genetically modified mouse model in which, at a mid-stage in life, we can prevent GIP from functioning in a specific region of the brain. We will then determine if inhibiting GIP’s function delays the development of ageing and extends a healthy lifespan. The knowledge acquired by this study could, in the long-term, contribute to the development of GIP-based treatments to improve health during ageing, thereby providing major long-term health benefits for New Zealanders.

Dr Matthew Jenkins
Psychological Medicine (UOW)
$399,975
Enhancing the health and wellbeing of rangatahi experiencing early psychosis

Psychosis is a disabling condition that has significant impact on quality of life and health and well-being, with disparities in physical health in particular being described as the ‘scandal of premature mortality’. Psychosis affects approximately 50,000 New Zealanders and disproportionately affects Māori, with an associated burden of care upon whānau. This project will be used to deliver and evaluate two components of a previously co-designed system of support aiming to support the health and well-being of rangatahi living with psychosis within early services. The first component focuses on the co-production of a web-based app as a platform for whanaungatanga amongst rangatahi whaiora and whānau, the sharing of lived experiences, and the signposting of local activities that might benefit rangatahi whaiora. The second component is a pilot 12-week health and well-being programme, which will be evaluated with regards to feasibility and acceptability within early intervention services.

Dr George Wiggins
Pathology and Biomedical Science (UOC)
$399,992
Advancing breast and ovarian cancer prevention strategies

Women at high-risk of breast and ovarian cancer need new and effective prevention strategies. Traditional options for cancer prevention include risk-reducing surgery, however this strategy is unwanted by many women due to a variety of reasons, such as fertility and menopause concerns. Providing doctors with a non-invasive and easily accessible preventative therapy for women at high risk of developing breast and ovarian cancer would have numerous benefits for the health system (e.g. reduced inequity in health outcomes), and for the patients and their whānau. Through a recent novel discovery in my laboratory, and collaboration with the world leading CIMBA Consortium, I am uniquely positioned to investigate potential novel preventative therapies for women at high-risk of breast and ovarian cancer. This innovative and potentially transformative research programme will provide a step towards reducing cancer diagnoses through the development of personalised preventative treatment(s).

Dr Samuel Wardell
Department of Microbiology & Immunology
$398,258
The role of antidepressants in promoting antibiotic resistance

In New Zealand and around the world, rates of antibiotic resistance in bacteria are rising. This is cause for alarm because once antibiotics stop working, even minor infections can become much more severe. Usually, when we think of how antibiotic resistance happens, the infecting bacteria evade and survive treatment with antibiotics and gain resistance to survive future treatments. However, new research studying how non-antibiotic medicines can cause bacteria to become antibiotic resistant as an unintended side-effect has opened a new area of research. This research looks to see if the highly prescribed group of medicines called antidepressants can increase antibiotic resistance in the body’s natural bacteria, and to determine whether these medicines could be unknowingly making the problem of antibiotic resistance worse. This research has the potential to fundamentally shift our understanding of how antibiotic resistance arises with hopes to reduce it in the future.

Dr Safina Gadeock
Department of Microbiology & Immunology
$400,000
Interferon-alpha targets as prognostic biomarkers for IBD patients

Inflammatory bowel diseases (IBD) are chronic debilitating intestinal diseases affecting 25,000 people in New Zealand, and costing about $245 million in healthcare annually. Anti-TNF antibodies are central to IBD therapy; however, most IBD patients lose responsiveness over time. During treatment, IBD patients responsive to anti-TNF antibodies have higher levels of the immunomodulatory cytokines, Type I IFNs (IFN-I), than non-responders. However, a role for IFN-I signalling pathways in driving regeneration associated responses of the intestinal lining (epithelium) in anti-TNF- treated IBD patients is unknown. We propose 1) to validate an innovative IFN-I biomarker panel to predict response to anti-TNFs in a cohort of NZ and US IBD patients; and 2) to elucidate the mechanism(s) driving IFN-I-dependent regenerative responses and epithelial barrier integrity in responsive IBD patients. This study will steer the development of an innovative biomarker panel that will help gastroenterologists tailor therapy for the approximately 50 per cent of non-responsive IBD patients.

Dr Jesse Kokaua
School of Biomedical Sciences
$506,978
Do the main drivers of poverty vary across Pacific ethnicities in Aotearoa?

The impact of poverty is felt profoundly on Pacific families. However, little is known on how relevant measures of poverty are to health outcomes in Pacific children. Most analyses of poverty in the Pacific assume current metrics of poverty apply uniformly to all Pacific ethnic groups. This proposal will investigate how poverty affects the health of Pacific children/families and if they are consistent across all Pacific specific groups. The study will take the form of four separate analyses in each Pacific community: describe morbidity and mortality for resident and non-residents; investigate associations between poverty and health in a birth cohort of children; predict health outcomes under different assumptions of poverty; and finally, undertake sense-making talanoa. Benefits from the study are specifically to Pacific communities but also to New Zealand overall.

Associate Professor Haizal Hussaini
Department of Oral Diagnostics & Surgical Sciences
$150,000
Retaining teeth for life: a smart stimuli-response dental pulp medication

Dental caries is a prevalent chronic disease in New Zealand; one in three adults has active dental caries. Caries lead to dental pulp infection, interfering with pulp regeneration and healing. Current therapies use cement-based calcium hydroxide which has limited success, and there is no biological treatment that can modulate inflammation and regenerate dental pulp. Recently, we have shown that by inhibiting IL-23, we can successfully treat inflamed pulp and regenerative healing. We aim to be the first to successfully deliver immunotherapy medication into the dental pulp using a smart stimuli-responsive hydrogel, controlling the inflammation and keeping the tooth vital. This research is a transformational way to treat dental pulp inflammation and caries without the need for expensive treatment.

Associate Professor Sara Filoche
Department of Obstetrics, Gynaecology and Women's Health (UOW)
$150,000
Building room for equity: Culture centred design of hospital waiting rooms

Hospitals in Aotearoa New Zealand have a legacy founded in colonialism and are designed to Eurocentric principles of health and well-being – as such they are inequitable by design and represent culturally unsafe spaces for many people who need to access them. Hospital waiting rooms represent one such space. Our project is premised on understanding how physical spaces in hospitals shape people’s experiences of care. Bringing culture centred design to hospital spaces holds potential as a new mechanism to supporting culturally safe healthcare practice. This project realises a new, unique collaboration between healthcare professionals, healthcare scientists, Māori health researchers and an indigenous design agency. It is the first of its kind in Aotearoa. The project will involve communities and health consumers through a kaupapa Māori design process to co-create a re-imagined virtual waiting room and inform healthcare environment design more broadly.

Associate Professor Ailsa McGregor
School of Pharmacy
$150,000
Preventing the ups and downs of lithium in bipolar disorder

Lithium is the gold-standard treatment for bipolar disorder and the only medication to reduce suicide risk. However, its effective dose is close to the toxic dose and frequent blood monitoring is required to prevent poisoning. Around half the individuals taking lithium stop their treatment due to adverse effects including kidney damage, weight gain and cognitive impairment. In a world first, we will ‘cage’ lithium with organic ligands to produce a delivery system with a quicker response and fewer side effects than current formulations. We will investigate the stability, release kinetics and biology of the novel complexes to identify a lead structure for further development and determine their social and cultural acceptability in preparation for future clinical trials. Providing proof-of-principle for a safer and more effective lithium medication that does not require blood monitoring has the potential to transform treatment and decrease the significant social and economic burden associated with bipolar disorder.

Dr Narun Pat
Department of Psychology
$150,000
Using multimodal MRI, genomics and AI to tackle ethnicity bias in neuroimaging

Technological advancements in machine learning and brain-MRI big data have led to rapid development of neuroimaging biomarkers useful for neurological/psychiatric disorders (e.g., Alzheimer’s and schizophrenia). But brain-MRI big data have predominantly been collected from non-diverse populations, mainly people of European descent. This has created an ethnicity bias: the neuroimaging biomarkers do not necessarily apply well to people not of European descent. For science to ensure equitable benefits for all, it needs to reflect the uniqueness of each of the world’s populations. We will harness the power of three novel interdisciplinary techniques to reduce the bias, including neuroimaging (i.e., combining different types of brain images), genomics (i.e., using genetic information to adjust the bias) and artificial intelligence (i.e., using deep-transfer learning to fine tune the biomarkers). Our project will radically change the way neuroimaging biomarkers are applied: as opposed to assumed universality, we can test the ethnicity bias and reduce it.

Dr Marina Kazantseva
Department of Pathology (Dunedin School of Medicine)
$150,000
Exploring the potential of the noncoding genome in lung disease diagnostics

Late diagnosis of chronic obstructive pulmonary disease (COPD) and lung cancer is particularly due to the lack of cheap, accurate and minimally-invasive tests, which could facilitate earlier and thus more successful treatment. Liquid biopsy is emerging as an important tool for lung disease early detection. The majority of the human genome consists of noncoding regions, harbouring functional elements that regulate expression of long noncoding RNAs (lncRNAs) that are key to lung disease development and progression. Our transformative idea is that altered chromatin characteristics within lncRNA genes regions can contribute to lncRNA genes expression and activity. Here we propose to use peripheral blood from healthy volunteers, COPD, and lung cancer patients to assess chromatin characteristics of lncRNA genes that may serve as blood-based biomarkers for early detection and treatment response in COPD and lung cancer. Our novel approach may lead to the development of new diagnostic strategies in lung disease.

Dr Kunyu Li
Department of Pathology (DSM)
$150,000
Using super-wideband microwave technology to improve cancer early diagnosis

Delays in cancer diagnosis significantly affect the outcomes of cancer treatments. Although concurrent application of both cancer imaging and molecular diagnostic techniques have enabled earlier cancer detection, there is a lack of clinical effectiveness and cost effectiveness of these cancer diagnostic modalities. In recent years, the application of microwave imaging (MWI) has been explored as an alternative and complementary tool to the current computer tomography (CT) and magnetic resonance imaging (MRI) for detecting tumours in an earlier stage. In this research, we propose to develop a new MWI approach using super-wideband (SWB) antenna, which offers many advantages over other types of MWI imaging approach. We will test the performance of this imaging system to detect tumours and monitor treatment response in mice bearing deep-seated and superficial tumours. This research has a strong potential for clinical translation and transformational change in cancer detection by enabling earlier and safer cancer screening.