Antibacterial Benzimidazole-2-Methanamines as Allosteric Modulators of <i>Streptococcus pneumoniae</i> Penicillin-Binding Protein 2x
The allosteric site of penicillin-binding protein 2x (PBP2x), an essential enzyme of cell-wall biosynthesis of <i>Streptococcus pneumoniae</i>, was targeted in virtual screening of >2 M compounds. A benzimidazole-2-methanamine hit emerged, which exhibited a modest minimal-inhibitory concentration (MIC) of 32 mg·L<sup>-1</sup>. A structure-activity campaign around the structural template resulted in evaluation of 96 compounds, leading to several analogs with MIC of ≤4 mg·L<sup>-1</sup>. These compounds exhibited a broad-based bactericidal growth inhibition against 31 clinical strains of <i>S. pneumoniae</i>.
Authors
- Neha Rana (ORCID: https://orcid.org/0000-0002-2259-6306)
- Shahriar Mobashery (ORCID: https://orcid.org/0000-0002-7695-7883)
- Mohini Mohan Konai (ORCID: https://orcid.org/0009-0003-5369-1597)
- Rhona Feltzer (ORCID: https://orcid.org/0000-0002-2071-1323)
- Jeshina Janardhanan (ORCID: https://orcid.org/0000-0003-4184-4325)
- Choon Kim (ORCID: https://orcid.org/0000-0003-0306-8935)
- Amr M. El‐Araby (ORCID: https://orcid.org/0000-0002-3143-8801)
- Mayland Chang (ORCID: https://orcid.org/0000-0002-4333-3775)
- Jed F. Fisher (ORCID: https://orcid.org/0000-0002-7174-4352)
- Van Trung Nguyen (ORCID: https://orcid.org/0000-0003-3070-7683)
- Homero Dominguez-Cisneros
Institutions
- University of Notre Dame (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-11-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c02273
- Primary Topic
- Pneumonia and Respiratory Infections
- Type
- article
- Field-Weighted Citation Impact
- 0.00