2. Academic Validation
  3. Identification of ethyl-6-bromo-2((phenylthio)methyl)imidazo[1,2-a]pyridine-3-carboxylate as a narrow spectrum inhibitor of Streptococcus pneumoniae and its FtsZ

Identification of ethyl-6-bromo-2((phenylthio)methyl)imidazo[1,2-a]pyridine-3-carboxylate as a narrow spectrum inhibitor of Streptococcus pneumoniae and its FtsZ

  • Eur J Med Chem. 2024 Mar 5:267:116196. doi: 10.1016/j.ejmech.2024.116196.
Kousar Jahan 1,  Rachana Rao Battaje 2,  Vidyadhar Pratap 3,  Ganesh Ahire 4,  Athira Pushpakaran 5,  Anvesh Ashtam 6,  Prasad V Bharatam 7,  Dulal Panda 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India. Electronic address: kousar02jahan@gmail.com.
  • 2 Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India. Electronic address: rachanabattaje@gmail.com.
  • 3 Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India. Electronic address: vdp0206@gmail.com.
  • 4 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India. Electronic address: ganeshahire351999@gmail.com.
  • 5 Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India. Electronic address: athirapushpakaran34@gmail.com.
  • 6 Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India. Electronic address: anveshashtam@gmail.com.
  • 7 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India. Electronic address: pvbharatam@niper.ac.in.
  • 8 Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, S.A.S. Nagar, Punjab, 160062, India; Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Mumbai, 400076, India. Electronic address: panda@iitb.ac.in.
PMID: 38350359 DOI: 10.1016/j.ejmech.2024.116196
Abstract

Filamentous temperature-sensitive mutant Z (FtsZ) is a key cell-division protein recognized as an important target for anti-bacterial drug discovery, especially in the context of rising multi-drug resistance. A respiratory pathogen, Streptococcus pneumoniae, is rapidly evolving Antibiotic resistance, thus posing a clinical risk in the developing world. Inhibiting the conserved protein FtsZ, leading to the arrest of cell division, is an attractive alternative strategy for inhibiting S. pneumoniae. Previously, Vitamin K3 was identified as an FtsZ-targeting agent against S. pneumoniae. In the present work, docking studies were used to identify potential anti-FtsZ agents that bind to the Vitamin K3-binding region of a homology model generated for S. pneumoniae FtsZ. Compounds with imidazo[1,2-a]pyridine-3-carboxylate core were synthesized and screened for their anti-proliferative activity against S. pneumoniae. Remarkably, the hit compound IP-01 showed anti-bacterial action against S. pneumoniae without any activity on Other bacteria. In S. pneumoniae, IP-01 showed similar inhibitory action on FtsZ and cell division as Vitamin K3. Sequence alignment identified three unique residues within S. pneumoniae FtsZ that IP-01 binds to, providing a structural basis for the observed specificity. IP-01 is one of the first narrow-spectrum agents identified against S. pneumoniae that targets FtsZ, and we present it as a promising lead for the design of narrow-spectrum anti-FtsZ anti-pneumococcal compounds.

Keywords

Anti-bacterial agents; Cell division inhibitor; FtsZ; Narrow-spectrum antibiotic; Streptococcus pneumoniae.

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