Innovative drug discovery approach addresses childhood diarrhoea in Africa

Iruka Okeke is a Nigerian Microbiologist and Professor of Pharmaceutical Microbiology at the University of Ibadan, Nigeria. She is a grantee of Grand Challenges Africa programme (GC Africa), which promotes Africa-led scientific innovations to help countries better achieve the Sustainable Development Goals by awarding seed and full grants to the continent’s most impressive solutions. GC Africa is implemented through the AESA Platform. AESA (The Alliance for Accelerating Excellence in Science in Africa) is a funding, agenda-setting, programme management initiative of the African Academy of Sciences (AAS) in partnership with the African Union Development Agency (AUDA-NEPAD), founding and funding global partners, and through a resolution of the summit of African Union Heads of Governments. GC Africa is supported by the Bill & Melinda Gates Foundation, Swedish International Development Cooperation Agency (Sida), and the German Federal Ministry of Education and Research (BMBF).

Summary

Half a million children die annually from diarrhoea and millions more are sickened or stunted, mostly in Africa and South Asia.  Prof Okeke and her team are working to understand the specific causes of diarrhoea to inform vaccine development and to design targeted treatments.

Efforts to combat childhood diarrhoea

Diarrhoea can result in formidable fluid lost and consequent dehydration that can kill, especially in young children. Development of simple means to replace lost fluid in children with diarrhoea in the mid-20th century significantly reduced the number of babies dying of infectious diarrhoea over the last three decades. However, this success is limited: the incidence of diarrhoea and diarrhoea-related death in the first year of life remains largely unchanged in most of Africa. Young children who survive repeated or protracted diarrhoea can suffer from malnutrition at the most critical point in their development. This in turn can lead to stunting, vulnerability to other illnesses and diminished quality of life, learning and productivity.  Much diarrhoea is underreported, to merely avert deaths is insufficient. There is a pressing need to prevent infections and shorten the course of this damaging condition, which is necessary to stand a chance of meeting the SDG3 target of reducing under-five mortality to below 25 per 1,000 live births by 2030 across Africa.

Prof Okeke’s bacterial genetics laboratory studies the causes of diarrhoea in young children, essential because bacteria that cause diarrhoea can be of little global interest because they predominantly affect vulnerable populations in low-income countries. Our group seeks to better describe disease-causing bacteria from harmless bacteria and to understand how bacteria cause disease and become resistant to existing therapies.

Childhood diarrhoea: simple condition, difficult problem

Half a million children die annually from diarrhoea and millions more are sickened or stunted, mostly in Africa and South Asia. These illnesses may be theoretically avoidable, but the poorest children are not adequately protected from diarrhoea. In Ibadan, most households depend on groundwater for household use, which is often tainted by harmful bacteria from human and animal waste; purified drinking water is expensive.

Developing targeted, high-impact interventions for diarrhoea is challenging because unlike tuberculosis or malaria, diarrhoea is not a specific disease: it is a syndrome caused by any of a hundred different microorganisms. Clean water and effective sanitation interventions hold the potential to combat the problem across bacteria types. Targeting the major causes of diarrhoea in a given area can additionally lead to the development of new technologies for context-specific tools. 

Too little is known about the causes of most childhood diarrhoeas in Africa. Global innovation is built on knowledge gleaned from the minuscule proportion of cases that occur in visiting tourists, rather than in African children. Our first essential task is to understand and address diarrhoeal disease in those that suffer from it most.

Leveraging science to design interventions against bacteria in diarrhoea

With an understanding of the specific causes of diarrhoea, it is possible to design treatments and develop targeted vaccines.  Molecular understanding of rotavirus, a major viral cause of childhood diarrhoea, has led to successes in vaccine development and use for those viruses. But many childhood diarrhoeas are caused by bacteria, for which vaccines are needed urgently.

Our studies of diarrhoea-causing bacteria seek to identify how harmful bacteria colonize. When these damaging bacteria produce diarrhoea, the protective bacteria that normally live inside us are killed by the harmful ones. The proteins that allow harmful bacteria to take hold are collectively known as adhesins.   

Diarrhoea is a flushing response by the body to remove harmful organisms from infected intestines. Children with diarrhoea must be kept hydrated whilst their natural defences fight against adhesins keeping bacterial invaders in place. Oral rehydration allows the intestine to fight harmful bacteria.  But what if we could actually help dislodge harmful bacteria?   Elimination of these colonizers might shorten, or even prevent, the adverse effects of diarrhoea.

Our laboratory is testing the unconventional notion that chemicals could disrupt adhesins used by bacteria to stay in place during diarrhoea. Proof of concept for the potential of such chemicals to be used for treatment is already emerging from research on other diseases similarly dependent on bacterial attachment, such as urinary tract infections. Such an approach to the treatment of diarrhoea could supplement current treatment.

The approach of targeting bacterial colonization, rather than bacterial survival, also reduces the chance of drug resistance, which is disabling antibiotics faster than new ones can be developed. And even when such chemicals do not meet the standards to make them candidates for development, they will contribute to our understanding of how adhesins work, contributing to vaccine development.