2. Academic Validation
  3. Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria

Development of narrow-spectrum topoisomerase-targeting antibacterials against mycobacteria

  • Eur J Med Chem. 2024 Jul 19:276:116693. doi: 10.1016/j.ejmech.2024.116693.
Maša Sterle 1,  Eva Habjan 2,  Martina Piga 1,  Peter Peršolja 1,  Martina Durcik 1,  Jaka Dernovšek 1,  Petra Szili 3,  Marton Simon Czikkely 4,  Nace Zidar 1,  Ilaš Janez 1,  Csaba Pal 3,  Tomaž Accetto 5,  Luis A Pardo 6,  Danijel Kikelj 1,  Lucija Peterlin Mašič 1,  Tihomir Tomašič 1,  Wilbert Bitter 2,  Andrej Emanuel Cotman 1,  Alexander Speer 7,  Anamarija Zega 8
Affiliations

Affiliations

  • 1 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia.
  • 2 Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VU Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands.
  • 3 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary.
  • 4 Synthetic and Systems Biology Unit, Institute of Biochemistry, Biological Research Centre, Szeged, H-6726, Hungary; Doctoral School of Multidisciplinary Medical Sciences, University of Szeged, Szeged, HU-6722, Hungary; Department of Forensic Medicine, Albert-Szent-Györgyi Medical School, University of Szeged, Szeged, HU-6722, Hungary.
  • 5 University of Ljubljana, Biotechnical Faculty, Department of Microbiology, Groblje 3, 1230, Domžale, Slovenia.
  • 6 Max Planck Institute for Multidisciplinary Sciences, Oncophysiology, Hermann-Rein-Str. 3, 37075, Göttingen, Germany.
  • 7 Department of Medical Microbiology and Infection Control, Amsterdam UMC, Location VU Medical Center, De Boelelaan 1108, 1081 HZ, Amsterdam, the Netherlands. Electronic address: a.speer@amsterdamumc.nl.
  • 8 University of Ljubljana, Faculty of Pharmacy, Aškerčeva cesta 7, 1000, Ljubljana, Slovenia. Electronic address: anamarija.zega@ffa.uni-lj.si.
PMID: 39053193 DOI: 10.1016/j.ejmech.2024.116693
Abstract

New 2-pyrrolamidobenzothiazole-based inhibitors of mycobacterial DNA gyrase were discovered. Among these, compounds 49 and 51, show excellent Antibacterial activity against Mycobacterium tuberculosis and Mycobacterium abscessus with a notable preference for mycobacteria. Both compounds can penetrate infected macrophages and reduce intracellular M. tuberculosis load. Compound 51 is a potent inhibitor of DNA gyrase (M. tuberculosis DNA gyrase IC50 = 4.1 nM, Escherichia coli DNA gyrase IC50 of <10 nM), selective for Bacterial topoisomerases. It displays low MIC90 values (M. tuberculosis: 0.63 μM; M. abscessus: 2.5 μM), showing specificity for mycobacteria, and no apparent toxicity. Compound 49 not only displays potent antimycobacterial activity (MIC90 values of 2.5 μM for M. tuberculosis and 0.63 μM for M. abscessus) and selectivity for mycobacteria but also exhibits favorable solubility (kinetic solubility = 55 μM) and plasma protein binding (with a fraction unbound of 2.9 % for human and 4.7 % for mouse). These findings underscore the potential of fine-tuning molecular properties to develop DNA gyrase B inhibitors that specifically target the mycobacterial chemical space, mitigating the risk of resistance development in non-target pathogens and minimizing harm to the microbiome.

Keywords

DNA gyrase; Mycobacterium abscessus; Mycobacterium tuberculosis; Nontuberculous mycobacteria; benzothiazole; inhibitor.

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