Prof.
Paul Cos
Department of Pharmaceutical Sciences, University of Antwerp, Antwerp, Belgium
Title: Targeting Mycobacterial Redox Systems: Why Drug Discovery Remains So Challenging
Mycobacterium tuberculosis is an intracellular pathogen that survives within host macrophages, where it is exposed to reactive oxygen and nitrogen species (ROS/RNS). To maintain redox homeostasis, the bacterium relies on mycothiol (MSH), a key antioxidant that detoxifies ROS by forming mycothiol disulfide (MSSM). The NADPH-dependent enzyme mycothiol disulfide reductase (Mtr) regenerates MSH from MSSM, thereby sustaining a reducing intracellular environment and supporting bacterial survival under stress.
This study investigates Mtr as a potential drug target by integrating genetic, biochemical, and structural approaches. Recombinant production and purification of Mtr were optimized to yield stable, high-quality protein suitable for assay development. A bioluminescence-based high-throughput screening (HTS) assay was developed and applied to a library of 137,000 compounds, resulting in 19 candidate inhibitors, including clustered chemotypes and fragment molecules. Selected hits were further evaluated in whole-cell and macrophage infection models. Functional validation studies using Mtr-deficient and knockdown strains demonstrated that reduced Mtr expression compromises bacterial growth, stress tolerance, and intracellular survival, particularly under acidic conditions mimicking the macrophage environment. Structural determination of Mtr from M. tuberculosis and related species provided the first atomic-level insights into this enzyme, enabling mechanistic studies and supporting structure-based drug design. Overall, this work establishes a robust discovery pipeline and highlights the challenges and opportunities in targeting redox metabolism for the development of novel anti-tubercular therapies.
Biography of the presenting author
Paul Cos received in 1995 a master’s degree in Pharmaceutical Sciences. In 2001, he became a Doctor in Pharmaceutical Sciences at the University of Antwerp, Belgium. After a post-doc fellowship at the Research Fund (FWO) – Flanders, I was appointed associate professor in 2009, professor in 2014 and full professor in 2020 at the University of Antwerp. As Professor at the University of Antwerp, I lead a multidisciplinary team studying biofilm-related and chronic infections. We develop standardized preclinical models, unravel tolerance mechanisms, and translate discoveries into new therapeutic strategies. Our work has yielded field-wide methodological guidelines, a patented antifungal therapy now in Phase 2 trials, and recent findings revealing widespread bacterial heterotolerance invisible to current diagnostics. I believe overcoming persistence and resistance requires integration across scales, disciplines, and perspectives. This principle also guides my role as Director of Business & Policy at FEMS, where I connect scientists, industry, and policymakers.
Over the past 25 years, I have built expertise in biofilm research, antimycobacterial drug discovery, and innovative therapies, publishing more than 270 papers (h-index 54). I enjoy mentoring the next generation of scientists (36 PhDs promoted) and sharing knowledge through teaching, international collaborations, and keynote lectures.
Presenting author details
Full name: Paul Cos
Contact number: 003232652628
Email: paul.cos@uantwerpen.be
ORCID: https://orcid.org/0000-0003-4361-8911
Website: https://www.uantwerpen.be/en/staff/paul-cos/