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Why Sulfur is Important in Lincosamide Antibiotics
Kelvin J Y Wu1,2, Elena V Aleksandrova3,2, Paul J Robinson1,2
1Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138, USA.
Chem
|August 11, 2025
Summary
The sulfur atom in cresomycin (CRM) is crucial for binding to bacterial ribosomes. Replacing sulfur with carbon or oxygen in CRM analogs reduced their antibacterial activity.
Area of Science:
- Medicinal Chemistry
- Molecular Biology
- Antimicrobial Resistance
Background:
- Cresomycin (CRM) is a synthetic lincosamide antibiotic effective against multidrug-resistant bacteria.
- Understanding the structure-activity relationship of CRM is essential for developing new antibiotics.
Purpose of the Study:
- To synthesize and characterize CRM analogs with sulfur atom replacements (C-CRM, O-CRM, Se-CRM).
- To investigate the impact of sulfur replacement on CRM's ribosomal binding and antibacterial activity.
Main Methods:
- Chemical synthesis of CRM analogs.
- High-resolution co-crystal structure determination of analogs bound to the bacterial ribosome.
- Assessment of target engagement and in vitro antibacterial activity.
Main Results:
- All four analogs (CRM, C-CRM, O-CRM, Se-CRM) adopted identical conformations on the ribosome.
- Only CRM and Se-CRM exhibited sulfur/selenium heteroatoms positioned for interaction with G2505.
- C-CRM and O-CRM showed reduced target engagement and antibacterial activity compared to CRM.
Conclusions:
- The sulfur atom in lincosamides like CRM plays a vital role in ribosomal binding.
- Sulfur replacement with carbon or oxygen negatively impacts antibiotic efficacy.
- The findings highlight the importance of the sulfur atom for effective antibiotic action against resistant bacteria.
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