DEPARTMENT FOR SCIENCE, INNOVATION AND TECHNOLOGY

Point-of-Care Innovative Sequencing Technologies and AI-Based Methods for Effective Diagnosis and Management of Antimicrobial Resistance in Leprosy

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Description

Antimicrobial resistance (AMR) in infectious diseases is increasingly recognized as a severe threat to global public health. AMR occurs when bacteria, viruses, fungi, and parasites evolve to resist the effects of medications, rendering standard treatments ineffective and leading to persistent infections. This resistance is fuelled by the overuse and misuse of antibiotics, poor infection control practices, inadequate sanitary conditions, and the global movement of people and goods. Leprosy, a chronic infectious disease characterized by granulomatous lesions affecting the skin and peripheral nerves, is caused by the bacterium Mycobacterium leprae (M. leprae). In 2022, approximately175,000 new cases were reported globally, predominantly in tropical regions. Standard treatment involves a multidrug regimen consisting of Dapsone, Rifampicin, and Clofazimine, administered over a duration of six months to one year. Since the 1960s, resistance to individual drugs has been observed, and recent findings indicate the emergence of multidrug-resistant M. leprae strains. As an obligate intracellular pathogen, M. leprae cannot be cultured in axenic media, necessitating the use of molecular diagnostics for detecting AMR. These diagnostics typically involve extracting M. leprae DNA, amplifying drug target genes via polymerase chain reaction (PCR),sequencing the amplicons to identify mutations, and performing bioinformatics analysis to determine the impact of the mutations on drug interactions and activity. While effective, this procedure requires advanced molecular/genomics laboratories, which are often unavailable in resource-limited settings, such as those in Southeast Asia. Additionally, the complexity and duration of in-vivo testing, which spans 6-8 months, make it impractical for routine diagnostic applications.Therefore, rapid, and accessible molecular diagnostic tools are crucial for effective disease management in endemic regions. The Philippines reports nearly 2,000 new leprosy cases annually. The absence of a decentralized diagnostic system for AMR in leprosy necessitates the development of innovative tools to ensure timely diagnosis and management. Understanding the mechanisms underlying AMR in leprosy is crucial for clinicians to identify alternative treatment regimens for drug-resistant cases. Leveraging our expertise in point-of-care compatible DNA amplification and sequencing technologies (Biomeme qPCR and Oxford Nanopore MinION based amplicon sequencing), along with our expertise in developing and maintaining sophisticated bioinformatics workflows and tools (such as HARP and HANSEN web databases), we propose the following objectives: WP1: Comparative evaluation of Biomeme qPCR and MinION-based DNAsequencing with conventional qPCR and DNA sequencing for detecting mutations in drug target-coding genes (rpoB, folP, gyrA, rpoC, fadD9, ribD, and nth) conferring AMR in leprosy. WP2: Development of a bioinformatics pipeline/workflow for the analysis of DNA sequencing data, determining mutations, and predicting the impacts of mutations on drug target protein structure, drug binding, and interatomic interactions. WP3: Decentralizing diagnosis of AMR in leprosy using point-of-care Biomeme qPCR and MinION-based DNA sequencing technologies at regional hospitals in the Philippines. WP4: Knowledge transfer, training, and capacity building of laboratory staff at the Department of Dermatology, Philippine General Hospital, and the College of Medicine, University of the Philippines, Manila. By advancing these innovative diagnostic tools and empowering local health systems, we aim to improve the management of leprosy and mitigate the impact of antimicrobial resistance in endemic regions.

Objectives

Antimicrobial resistance (AMR) in infectious diseases is increasingly recognized as a severe threat to global public health. AMR occurs when bacteria, viruses, fungi, and parasites evolve to resist the effects of medications, rendering standard treatments ineffective and leading to persistent infections. This resistance is fuelled by the overuse and misuse of antibiotics, poor infection control practices, inadequate sanitary conditions, and the global movement of people and goods. Leprosy, a chronic infectious disease characterized by granulomatous lesions affecting the skin and peripheral nerves, is caused by the bacterium Mycobacterium leprae (M. leprae). In 2022, approximately175,000 new cases were reported globally, predominantly in tropical regions. Standard treatment involves a multidrug regimen consisting of Dapsone, Rifampicin, and Clofazimine, administered over a duration of six months to one year. Since the 1960s, resistance to individual drugs has been observed, and recent findings indicate the emergence of multidrug-resistant M. leprae strains. As an obligate intracellular pathogen, M. leprae cannot be cultured in axenic media, necessitating the use of molecular diagnostics for detecting AMR. These diagnostics typically involve extracting M. leprae DNA, amplifying drug target genes via polymerase chain reaction (PCR),sequencing the amplicons to identify mutations, and performing bioinformatics analysis to determine the impact of the mutations on drug interactions and activity. While effective, this procedure requires advanced molecular/genomics laboratories, which are often unavailable in resource-limited settings, such as those in Southeast Asia. Additionally, the complexity and duration of in-vivo testing, which spans 6-8 months, make it impractical for routine diagnostic applications.Therefore, rapid, and accessible molecular diagnostic tools are crucial for effective disease management in endemic regions. The Philippines reports nearly 2,000 new leprosy cases annually. The absence of a decentralized diagnostic system for AMR in leprosy necessitates the development of innovative tools to ensure timely diagnosis and management. Understanding the mechanisms underlying AMR in leprosy is crucial for clinicians to identify alternative treatment regimens for drug-resistant cases. Leveraging our expertise in point-of-care compatible DNA amplification and sequencing technologies (Biomeme qPCR and Oxford Nanopore MinION based amplicon sequencing), along with our expertise in developing and maintaining sophisticated bioinformatics workflows and tools (such as HARP and HANSEN web databases), we propose the following objectives: WP1: Comparative evaluation of Biomeme qPCR and MinION-based DNAsequencing with conventional qPCR and DNA sequencing for detecting mutations in drug target-coding genes (rpoB, folP, gyrA, rpoC, fadD9, ribD, and nth) conferring AMR in leprosy. WP2: Development of a bioinformatics pipeline/workflow for the analysis of DNA sequencing data, determining mutations, and predicting the impacts of mutations on drug target protein structure, drug binding, and interatomic interactions. WP3: Decentralizing diagnosis of AMR in leprosy using point-of-care Biomeme qPCR and MinION-based DNA sequencing technologies at regional hospitals in the Philippines. WP4: Knowledge transfer, training, and capacity building of laboratory staff at the Department of Dermatology, Philippine General Hospital, and the College of Medicine, University of the Philippines, Manila. By advancing these innovative diagnostic tools and empowering local health systems, we aim to improve the management of leprosy and mitigate the impact of antimicrobial resistance in endemic regions.

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Location

The country, countries or regions that benefit from this Programme.

Philippines

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