Boosting the efficacy of anti-MRSA β-lactam antibiotics via an easily accessible, non-cytotoxic and orally bioavailable FtsZ inhibitor.

The rapid emergence of methicillin-resistant Staphylococcus aureus (MRSA) strains has undermined the therapeutic efficacy of existing β-lactam antibiotics (BLAs), prompting an urgent need to discover novel BLAs adjuvants that can potentiate their anti-MRSA activities. In this study, cytotoxicity and antibacterial screening of a focused compound library enabled us to identify a compound, namely 28, which exhibited low cytotoxicity against normal cells and robust in vitro bactericidal synergy with different classes of BLAs against a panel of multidrug-resistant clinical MRSA isolates. A series of biochemical assays and microscopic studies have revealed that compound 28 is likely to interact with the S.

New application of tiplaxtinin as an effective FtsZ-targeting chemotype for an antimicrobial study.

The filamenting temperature-sensitive mutant Z (FtsZ) protein is generally recognized as a promising antimicrobial drug target. In the present study, a small organic molecule (tiplaxtinin) was identified for the first time as an excellent cell division inhibitor by using a cell-based screening approach from a library with 250 compounds. Tiplaxtinin possesses potent antibacterial activity against Gram-positive pathogens.

Efficient Synthesis of Amine-Linked 2,4,6-Trisubstituted Pyrimidines as a New Class of Bacterial FtsZ Inhibitors.

We have recently identified a new class of filamenting temperature-sensitive mutant Z (FtsZ)-interacting compounds that possess a 2,4,6-trisubstituted pyrimidine-quinuclidine scaffold with moderate antibacterial activity. Employing this scaffold as a molecular template, a compound library of amine-linked 2,4,6-trisubstituted pyrimidines with 99 candidates was successfully established by employing an efficient convergent synthesis designed to explore their structure-activity relationship. The results of minimum inhibitory concentration (MIC) assay against strains and cytotoxicity assay against the mouse L929 cell line identified those compounds with potent antistaphylococcal properties (MIC ranges from 3 to 8 μg/mL) and some extent of cytotoxicity against normal cells (IC ranges from 6 to 27 μM).