Grants awarded: Affordable Healthcare in India

Project summaries of Wellcome grants awarded under the scheme ‘Affordable Healthcare in India’.

High sensitivity multiplex point-of-care assay system for the detection of blood borne infections in emergency settings

Better feasibility of rapid test kits for infectious diseases can be achieved by improving the analytical sensitivity of the test kits in order to detect maximal amount of the infected individuals. With a combination of engineered binder molecules, traditional LFA-membranes and highly detectable reporter particles, the analytical sensitivity of the tests can be improved to match the tests currently done in centralized laboratories. These high-performance rapid test-kits can potentially broaden the selection of infectious diseases that can be tested in near-patient conditions.

The project aims to produce - i) an easily operated and reliable multiplex assays with plastic cassettes for the mentioned analytes (HIV, HCV and HBV); ii) incorporate up-converting nanoparticle (UCP) reporter technology in the produced assays to achieve maximal assay sensitivity and; iii) produce affordable mass-producible reader device to measure and interpret assay signals to interpret test results. Dr Gaurav Batra of The Translational Health Science & Technology Institute (THSTI) leads a collaboration involving The International Centre for Genetics Engineering & Biotechnology (ICGEB), University of Turku, Kaivaogen, and Designinnova. 

The team aims to produce a new technology concept which upgrades the performance of the currently used rapid-testing methodology with lateral flow assay (LFA) test kits. The goal is to test infectious diseases including HIV, HBV and HCV in near-patient conditions with high accuracy and reliability without sacrificing the affordability of the testing.

Evaluating the efficacy and safety of an innovative and affordable goat lung surfactant for the treatment of respiratory distress syndrome in preterm neonates: a multi-site randomized clinical trial

Surfactant is a natural compound that helps in proper exchange of gases. However, preterm neonates do not produce enough quantity of surfactant resulting in difficult breathing. Many such neonates succumb to this disease.

Treatment of such babies with surfactant obtained from animals can save these babies. Despite the availability of surfactant in developed nations since 1990s, most parents in India and other low and middle income countries (LMICs) cannot afford it due its high cost. AIIMS, New Delhi team developed an indigenous surfactant (GLSE) from the lungs of slaughtered goats. The product was standardized by a Cadila Pharmaceuticals, India. Pre-clinical studies have found GLSE to be as efficacious and as safe as the standard product.

A team led by Dr Ramesh Agarwal, at the All India Institute of Medical Sciences, New Delhi, plan to compare safety and efficacy of GLSE to a standard product (Survanta) in 900 preterm neonates at twelve academic institutions in India. Eligible neonates would receive GLSE or Survanta and followed up for 8-12 weeks to study safety and efficacy outcomes. Clinical Development Service Agency (CDSA) of and other eminent experts would monitor the trial. If GLSE is proven to be safe and efficacious, it would serve as an affordable product to a large section of population in India and possibly other LMICs.

Affordable standing wheelchair

For wheelchair users, standing up on a regular basis is necessary to prevent secondary problems and maintain good health. However, this task is very challenging - typically the person has to wear lower-limb orthoses and then be helped up by others to the standing position. This project's goal is to further develop and commercialize a manual wheelchair with integrated stand-up capability that is affordable and accessible to the vast majority of wheelchair users in India. The proposed wheelchair design will allow the occupant to raise oneself from a sitting position to an upright one using their own muscle power.

In addition to medical benefits, a standing wheelchair can enable users to be more independent in activities of daily living. It can reduce a wheelchair user's reliance on others to reach shelves, cupboards or switches, for instance. The ability to stand and have a better reach can open up more career opportunities as well. It can also help a user psychologically to be able to stand, make eye contact and talk face-to-face with other people at events. Thus an affordable, easily-actuated standing mechanism incorporated into a wheelchair can significantly improve the quality of life for an user by integrating therapy with mobility and providing greater independence. This project will be led by Dr Sujatha Srinivasan and colleagues at the Indian Institute of Technology Madras, working in partnership with Phoenix Medical Systems and the Association of People with Disability.

The ReMotion Knee: Affordable and user-centric knee joint to remobilised above-knee amputees in India and globally

Dr Krista Donaldson, CEO of the non-profit product development company D-Rev, has received funding from the Wellcome Trust to support the development of a new knee that will interface with the International Committee of the Red Cross (ICRC) prosthetic system, as well as the final testing and manufacture of the ReMotion Knee. Co-principal investigator Dr Pooja Mukul of the Jaipur Foot Rehabilitation Centre (BMVSS) in India, will jointly manage this project.

The Knees will first be made available in the Indian market, which it is hoped will serve as a model for the delivery of affordable, high quality medical devices to patients in low-income regions globally. The prosthetic knee joints are designed for above-knee amputees who are unable to access or afford high-quality leg systems. D-Rev will pursue the goal of reaching as many poor amputees as possible in India, and around the world. With the support of the Jaipur Foot Rehabilitation Centre, D-Rev will also carry out programs allowing training institutions to purchase and learn from ReMotion and improve the practice of how amputees are fitted by prosthetists. 

See also:  A ReMotion Knee film

Development of a novel therapy for the treatment of Multiple Drug Resistant and Extensively Drug Resistant Tuberculosis

India has the world’s highest burden of tuberculosis and had approximately 66,000 MDR-TB cases among notified pulmonary TB cases in 2011. Treatment for MDR-TB is expensive, has greater risks of side effects, and lasts 18-24 months, with a large number of patients who must access treatment without financial assistance. Hence there is urgent need for the development of new anti TB drugs that are cheaper, effective against MDR-TB and additionally easily available, with the potential of shorter treatment period.

The Wellcome Trust has funded a team from Sphaera Pharma and the Drug Discovery Research Centre (DDRC) of the Translational Health Science and Technology Institute to evaluate the utility of SPR113 as a drug for the treatment of MDR- and XDR-TB in preclinical and clinical studies. By targeting a host factor SPR113 works through a different mechanism than existing TB drug which means that it has the potential to make TB therapy shorter and more effective and less likely to result in the development of resistance when used in conjunction with current therapies.

SmartSense Multianalyte sensing device for management of Diabetic Kedoacidosis (DKA)

Diabetic Ketoacidosis (DKA), an acute complication of diabetes, is presented with acute changes in physiological parameters like blood glucose, salts and acidity of blood. Presently they are sensed using different chemical analysers for different analytes, which not only consumes a lot of resources and money but also precious time. Timely diagnosis and immediate treatment modifications is essential to the effective management of DKA.

In developing nations like India, it is practically impossible to get all the tests done within an hour to provide effective management leading to increased morbidity and mortality. To solve this problem a team led by Professor Rohit Srivastava at IIT Bombay intend to develop an all-in one solution for management of DKA using multi-parameter detection sensors and an indigenously developed reader device. The intended reader device is already prototyped and is low-cost and highly accurate being based on fluorescence.

The first key goal is to develop and validate the three biosensors (glucose, salts and acidity) essential for the management of DKA. Second primary goal is to validate the sensors using the indigenously developed reader device. Other key goals include the development and validation of the urea and bicarbonate sensor along with the pilot validation of the complete device at a tertiary health centre.

Testing of a novel Continuous Positive Airway Pressure (CPAP) machine to promote rational oxygen use for neonates and to reduce the incidence of retinopathy of prematurity (ROP) in India

Respiratory distress is a leading cause of mortality among premature and low birth weight babies and bubble CPAP (continuous positive airway pressure) is one of the key tools clinicians can use to treat it. Unfortunately the bubble CPAP technology that is widely available in high-income countries is not appropriate for India and other low- and middle-income countries because existing devices are too fragile, are expensive to purchase, require costly consumables, and use difficult-to-source inputs like compressed medical air.

The Wellcome Trust has made an Affordable Healthcare award to Thrive Networks (formerly East Meets West Foundation), a California-based NGO, and Medical Technology Transfer and Services (MTTS), a Vietnam-based social enterprise, who have teamed up to develop, test and bring to market a bubble CPAP device that will make this life-saving technology affordable and accessible to hospitals throughout India. Bangalore-based M.S. Ramaiah Medical College is also contributing to the project.

The Thrive Networks CPAP will provide heated, humidified, blended air; will be durable and easy to operate; and will feature an on-board air compressor and built-in pulse oximeter. The device will also be compatible with battery and solar energy, making it suitable for use in regions with an unstable electricity supply. 

The newly developed bubble CPAP will use tubing sterilizable for each patient, therefore reducing the need for consumables and drastically lowering lifetime operating costs, while also reducing risk of infection from re-use of tube sets meant to be disposable, a common practice in resource-limited hospitals. The new bubble CPAP anticipates the challenges present in low-resource settings in India and offers hospitals the capacity to provide cost-effective, appropriate treatment for vulnerable newborns suffering from respiratory distress.

PURAK: Wearable Devices for Distal Arm Functionality Rehabilitation

The loss of an arm and hand through amputation following an accident has a drastic effect on the victim. If the victim is also the main wage earner in a family, as is frequent in India, the impact on dependents can be even greater. Providing the victim with a prosthetic hand and rehabilitation at an early stage can boost their chances of regaining ability with their arm and returning to productive work.

However prostheses are either not affordable for the large majority of the Indian population or unsuitable for sustainable use and maintenance. The Indian Institute of Science, Bangalore (IISc) has made a breakthrough with new concepts for the design of affordable prostheses. An international collaboration has been formed between the IISc and the University of Oxford with the aim of developing these designs and readying them for commercial manufacture.

The IISc, with its expertise in affordable and appropriate design, will work together with biomechanics and clinical trials experts at the University of Oxford and with experts in commercialisation at both centres. This international partnership will ensure the new design ideas from IISc have a major impact on affordable healthcare in India.

Affordable refreshable Braille displays based on shape memory actuation

Refreshable Braille Cells or RBCs are critical for accessing digital content by the visually impaired. The only other alternative is voice output using text-to-speech engines. Being a software only solution, the products are economical but do not promote active reading and writing. In fact it is widely accepted in the community that voice readout of digital text should supplement not replace active reading and writing which is essential for comprehensive learning.

RBCs based on piezoelectric transducers have been commercially available for more than two decades. The devices due to its high cost have no penetration in the developing countries and even in developed countries has a small market. IIT Delhi has developed RBCs based on shape memory alloy (SMA wires) that can potentially reduce the costs by tenth or even more. Further, they have also designed display systems using current day low cost controllers and other sensors.

Together with low cost RBCs, it should be possible to reduce the overall cost of the comparable systems by more than fifth of current costs. This is not only likely to create a tremendous new market in the developing world where most of the visually impaired reside but also significantly expand the market even in the developed world.

In this project sponsored by Wellcome Trust, IIT Delhi is partnering with the Phoenix Medical Systems, Chennai; KritiKal Solutions Pvt. Ltd, Noida; and the Saksham Trust, Delhi to prototype and validate the RBCs as well as RMC based display systems. The Phoenix Medical Systems will absorb the IIT Delhi's RBC technology to produce RBCs, whereas KritiKal Solutions will be prototyping the display systems based on these cells for functional validity and user trials.

The Saksham Trust is an organization committed to creating and disseminating technology solutions for the visually impaired and has a large network of partners in the country. This will be leveraged for taking user feedback as well as conducting large scale validation trials before the product is launched at the end of the project.

Pre-clinical development of an affordable, safe and efficacious four-in-one dengue vaccine candidate  

Dengue poses a significant global public health risk to 3.6 billion people in more than 150 countries. A recent study estimates that Dengue has infected ~400 million people globally in the year 2010, of which 34% were people in India.

A vaccine against dengue remains an unmet healthcare need in India and world-wide. Anti- DENV antibodies which are cross-reactive, but not cross-protective, tend to exacerbate disease through antibody-dependent enhancement (ADE). For a useful dengue vaccine, safety and efficacy are inter-linked and a dengue vaccine therefore needs to simultaneously protect against all four DENVs. The major thrust of efforts in the past several decades has been on the development of Live-Attenuated-Vaccines (LAV). The persistent difficulty of various dengue LAV candidates in eliciting a balanced immune response against all the four serotypes has serious safety implications.

With the support of an Affordable Healthcare in India Award, Dr Navin Khanna at the International Centre for Genetic Engineering and Biotechnology, India (‘ICGEB’) will be aiming to develop an affordable, safe and efficacious ‘four-in-one’ dengue subunit vaccine candidate (DSV4). The vaccine is based on a non-replicating VLP platform presenting EDIIIs of all four DENVs in a single entity and uses the high capacity P. pastoris expression system. The project involves process development and pre-clinical studies of this novel vaccine candidate in a dengue sensitive mouse model.

m-WELLCARE: an integrated mhealth system for the prevention and care of chronic diseases

Cardiovascular Diseases (CVDs) account for a third of total mortality in India and are projected to increase dramatically. Common modifiable risk factors for CVDs can be detected early and can be controlled by cost effective, widely available interventions.

The major barriers to controlling these conditions in India and elsewhere are low detection rates, inadequate use of evidence based interventions and low adherence with these interventions. Common mental disorders such as anxiety and depression are frequently co-morbid with CVDs risk factors and often contribute to failure to follow treatment plans. Primary health care is the appropriate setting for improving the prevention and management of these chronic conditions. 

Public Health Foundation of India  and the London School of Hygiene and Tropical Medicine will develop and evaluate an innovative mobile health (mhealth) software application, m-WELLCARE, which provides a patient health profile, decision support for clinical care, monitoring and feedback for use in Indian Community Health Centers (CHCs). This research will follow the steps proposed by the MRC for evaluation of complex interventions. Technical development of mwellcare will be conducted, user acceptability appraised and potential barriers overcome. m-WELLCARE will be evaluated in CHCs of Harayana and mini-primary health centers of Tamil Nadu. The use made of mwellcare, its impact on patterns of health care received and changes in risk factors achieved will be evaluated. In parallel a business plan will be established to enable the scaling up and sustainability of mwellcare.

Development of a rapid system for diagnosing corneal infections using pathogen-responsive polymers

Infectious diseases of the eye are a common cause of ocular damage and blindness in India. Early diagnosis and initiation of appropriate treatment are key to reduce both of these negative outcomes. The cause of these infections varies throughout the globe (with a marked contrast between India and the UK) and, therefore, correct identification of the infecting agent plays a crucial role in successful treatment.

While clinical examination of eye infections can provide clues, the identification of the causative microbe requires facilities that are not widely available in India. In practice many clinicians do not perform microbiological testing and treat patients following empirical observations. This approach not only delays definitive therapy but also can result in failure to arrest the infection or causes corneal damage from toxicity of the various agents used indiscriminately.

The joint team led by Dr Prashant Garg at the L. V. Prasad Eye Institute in Hyderabad, India and Professor Stephen Rimmer at the University of Sheffield in England seek to apply smart polymer technology to the detection of infection in human eyes. The project will develop the use of specialised contact lenses made of highly branched polymers functionalised with end groups that bind specifically to either Gram-negative bacteria, Gram-positive bacteria or fungi. The binding with microorganisms can be detected by adding solutions that change colour depending on the bound microorganism. It is hoped that these new ophthalmic devices will provide a rapid point of care diagnosis of both bacterial and fungal infections allowing step changes in treatment.

Affordable mechanical ventilation for emerging market

Respiratory illness is a leading cause of hospitalisation and death in emerging nations. Each year thousands of patients die in rural community hospitals because of lack of access to mechanical ventilation. Influenza is especially devastating, affecting newborns and the elderly disproportionately.

Despite improvements in infrastructure and economies, ventilators remain out of reach for many hospitals. OneBreath is a Silicon Valley start-up conquering one of the most difficult problems in rural critical care: delivering high precision, high reliability and low cost in a mechanical ventilator. Vaatsalya is a healthcare company focused on delivering quality healthcare services across semi-urban and rural India. Together, Dr Ashwin Naik of Vaatsalya and Dr Matthew Callaghan of OneBreath are developing a novel ventilator specifically addressing the needs of hospitals serving India’s lower income populations.

Insecticide Quantification Kits (IQK) for Vector Control Programmes in India

Visceral leishmaniasis (Kala Azar) and malaria are deadly diseases that are widespread in the Indian subcontinent.  Since they are transmitted by sandfly and mosquito vectors respectively, insecticides are the most effective way to control these diseases, but only if the correct amount of insecticide is deposited on the sprayed surfaces.

Too little and the sand flies and mosquitoes will survive and become resistant to the insecticide, too much and human health and the environment can suffer. Unfortunately, monitoring insecticides is an expensive process involving sophisticated equipment or complex biological assays. Therefore, it is not routinely done, putting populations at increased risk of disease.

Dr Pradeep Das and his team at the Rajendra Memorial Research Institute of Medical Sciences in Patna (RMRI) are involved with the eradication of Kala Azar in northern India and bordering countries. Simple visual assays (quantification tests) for the rapid and reliable monitoring of DDT, carbamate and organophosphate, the classes of insecticide commonly used against sand flies and mosquitoes, have been developed by Dr Paine and colleagues at the Liverpool School of Tropical Medicine (LSTM),using funding obtained through the Innovative Vector Control Consortium (IVCC). 

RMRI and LSTM have been awarded Affordable Healthcare Funding to join forces in developing these assays further and establishing them as convenient tools (Insecticide Quantification Kits) for monitoring the quality of indoor residual spray programmes against insect borne diseases in India and elsewhere. This will involve assay refinement, kit development and field trials to demonstrate kit effectiveness, practicality and reliability. The goal is to provide field operatives with simple visual rapid tests for the precise monitoring of insecticides to maximise the benefits from vector control and minimise the risks to public health and the environment.

Affordable, battery operated, digital screening devices for preventable blindness

The World Health Organisation estimates that there are nearly 285 million people globally who are visually impaired, and at least 75% of them have conditions that are reversible, treatable and/or preventable. Nearly 90% of these individuals are in small towns and villages in many of the developing nations, including India.

Many of the current diagnostic tools available for screening are centralised in their availability, are expensive and often difficult to use in resource or infrastructure-starved areas.  In order to tackle this, Remidio, a product design and development company headquartered in Bangalore has developed a battery operated, handheld, digital and non-digital ophthalmoscope, with several unique features. The company involves key stakeholders during the product development process – clinicians, patients, technicians and community health workers, with a view to designing easy-to-use, product solutions that work within the constraints of a developing nation context. Affordability, robustness for everyday use in the field, portability, battery operation, and a customer-driven simplicity of use, differentiate the products Remidio brings to market.

The retinal imaging products from Remidio are based on a fundamental illumination technology patent. The novel illumination design enables high quality, reflex-free retinal imaging in a compact, portable format, with minimal number of optical elements. The digital systems have been designed to allow for remote review of captured images, allowing for the implementation of scalable models for the decentralised screening and detection of diseases as diverse as Diabetic Retinopathy, AMD, and Glaucoma. This project aims to complete the development and evaluation of the clinical performance of the digital imaging systems.  These devices aim to fill a critical unmet-need in public-health screening for preventable blindness.

Development and impact assessment of an mHealth package for rural India focusing on reproductive, maternal and child health, in support of the Government of India National Rural Health Mission

FRHS, Columbia University and WHO have been awarded translational funding to develop and create an “mHealth Package” to facilitate and support various aspects of rural health workers’ work and enabling a flow of communication between community members, health workers and health facilities.

India's rural, economically poor populations depend on health care provided by outreach and facility-based workers. But the current health management information system (HMIS) under the National rural Health Mission (NRHM) is failing to optimise these workers' performance: significant weaknesses in the predominantly paper-based HMIS are resulting in inefficiencies, inaccuracies, data under-utilisation and, crucially, missed opportunities for worker support, motivation and improvement, resulting in poor health outcomes. Mobile technologies offer the promise of enormous advances in such environments, with the potential to empower health workers through instantaneous communication and feedback, delivery of up-to-date educational content, alerts and reminders, remote support from experts and performance monitoring.

This project, to be piloted in Karnataka state, under the supervision of Dr Nirmala Murthy, will develop an "mHealth Package" - a strategic mix of mobile technology applications and support materials - to support NRHM reproductive, maternal and child health (RMCH) services. The technology will emphasise ease of use by low-literacy individuals, will be provided free of charge, and is envisaged for massive scale-up following rigorous pilot testing, impact assessment and revision. The resultant intervention will empower rural health workers and their clients along the continuum of RMCH care, integrating and streamlining data with existing HMIS standards for enhanced provider performance and population health outcomes.

Development of Smart Cane, an affordable above-knee obstacle detection and warning system for the visually impaired

The Indian Institute of Technology (IIT) Delhi has developed the Smart Cane, a navigation and mobility aid for visually challenged people. The Smart Cane is an innovative device that can be mounted on a traditional white cane to enhance its functionality, resulting in improved mobility and safety, while reducing dependence on sighted assistance.

White canes are currently the most commonly used visual mobility aid; however, a white cane can only detect certain types of obstacles within a limited range and cannot detect obstacles that are above the knee  (e.g. a steel bar on the road) or protruding (e.g. a tree branch or an open window). The Smart Cane device uses ultrasonic sensors to detect obstacles up to 3m away, and the range of the detected obstacles is conveyed using vibratory signals with different vibration characteristics. It is designed as a user-detachable unit and is powered by rechargeable Li-ion battery. The design emphasis has been on making an affordable device, and it is currently expected to cost less than Rs 2000 (£30) to the end user.

This project targets the design of a manufacturable device, optimising it based on user feedback from field trials and making it ready for regulatory approvals and certification. It has been proposed that extensive user trials should be carried out at multiple locations in the next 18 months. The project is being jointly undertaken by IIT Delhi with an industrial partner, Phoenix Medical Systems (P) Ltd, Chennai. The third partner in the project is Saksham Trust, New Delhi, who have domain expertise and links to the network of organisations working for the visually impaired.

Chest compression device for patients with sudden cardiac arrest

Professor Bhargava and his colleagues at the All India Institute of Medical Sciences (AIIMS), New Delhi, have developed a preliminary prototype of a novel chest compression device that uses compression and decompression cycles uniquely.

Sudden cardiac arrest (SCA) is the abrupt cessation of heart pump function. This causes an inadequate blood supply to the vital organs of the body. If corrective measures are not taken immediately, this condition rapidly progresses to death. Manual compression of the centre of the chest (sternum) during cardiopulmonary resuscitation (CPR) is the 'gold standard' for managing such patients. Improving cerebral and coronary perfusion still remains a challenge during CPR.

Professor Bhargava and his colleagues at the All India Institute of Medical Sciences (AIIMS), New Delhi, have developed a preliminary prototype of a novel chest compression device that uses compression and decompression cycles uniquely. The [Affordable Healthcare] funding will be used in two phases. In phase-I, the concept will be refined and a prototype will be developed. In phase-II, feasibility studies and validation will be performed in animal models.

Development of a synthetic biodegradable cell carrier membrane for the transplantation of cultured cells or freshly excised autologous tissue (limbal segments or oral mucosa) for diseases of the cornea

The LV Prasad Eye Institute in Hyderabad, in partnership with Sheffield University, has been awarded funding to develop and use new biocompatible materials for a stem-cell-based therapy to restore sight in eyes where the cornea has been damaged by chemical injury or burns.

This advanced tertiary eye care centre in Hyderabad offers high-quality, comprehensive eye care on an equitable basis, to millions across the state of Andhra Pradesh, through its pyramidal network that involves 17 secondary eye care centres in towns and 65 primary care centres in large villages, in remote rural areas. The centre at Hyderabad has so far provided limbal stem-cell-based therapy to over 700 patients.

The international programme to evaluate the Polycap in a large randomised controlled clinical trial in a primary prevention setting

Cadila Pharmaceuticals Ltd are investigating the concept of a combination pill for the control of cardiovascular disease in the primary prevention setting, through a Phase III clinical trial.

The pill (Polycap) will comprise a mixture of three blood pressure reducing agents - a diuretic (hydrochlorothiazide), an ACE inhibitor (ramipril)  a beta blocker  (Atenolol), and a cholesterol lowering statin (simvastatin). All of the agents were chosen based on the evidence of their reducing cardiovascular disease risk and their generic drug status.

Cadila’s pioneering work in this area has been to develop stable pharmaceutical compositions in a Polycap formulation. They will work with a group of experienced clinical collaborators including Salim Yusuf, Professor of Medicine at McMaster University, to undertake a study with 5000 subjects (without a history of previous heart attack or stroke) over five years. 

The proposed placebo-controlled study will recruit individuals (men over 55 and women over 60) with a INTERHEART risk score (obtained through a questionnaire based on family history and lifestyle factors) greater than a threshold value with a estimated yearly primary event rate of 0.75 to 1 per cent. The primary outcome will be a composite of CV death, non-fatal MI and non-fatal stroke.

Novel candidate drugs against M. tuberculosis: design, validate and optimise leads targeting NAD(P)(H) utilizing enzymes.

AstraZeneca and AstraZeneca India have been awarded translational funding to identify lead compounds of novel structural classes capable of inhibiting NAD metabolism, as candidate drugs for the treatment of Mycobacterium tuberculosis.

Curative tuberculosis therapy requires killing a 'difficult-to-treat' residual population of non-replicating organisms. Significant evidence now suggests that NAD metabolism is an essential factor in the survival of non-replicating M. tuberculosis bacilli and thus provides a rare opportunity to drive a discovery program directly addressing sterilising capability. The programme aims to inhibit NAD(P)(H)-utilising enzymes, including those involved in the biosynthesis of NAD, by competing with the NAD binding domain, using NAD mimetic libraries.

The programme of work is based on a NAD mimetic pilot study that identified a number of lead-like scaffolds with promising activity and selectivity. Building from the molecular starting point library used in the pilot study, a second generation library will be created and tested in a screening cascade which blends the strengths of target-based optimisation with the power of whole cell screens. The design of the primary library involves pharmacophore and substructure overlap together with the mapping of key interactions between NAD and the cognate binding site, based on known co-crystallisation studies.

The screening cascade is designed to build on the strengths of (a) target-based approaches (early structural knowledge facilitates compound optimization) and (b) whole cell screening (early proof of whole cell activity ensures drug-like behaviour in all early series). The key challenge in targeting the ubiquitous NAD molecule is to introduce specificity. The literature precedence and AstraZeneca’s initial work suggest that this is achievable.