Targeting FtsZ for antibiotics discovery

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We focused on the development of novel drugs against drug-resitant pathogens, including multidrug-resistant Mycobacterium tuberculosis (MDR-TB), methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VRE). The following two subprojects were undertaken.Screening of extracts from a marine microbial culture collection for inhibition of FtsZ action in M. tuberculosis: A bacterial tubulin homologue, FtsZ, is an essential cell division protein that polymerizes in a GTP-dependent manner, forming a cytokinetic ring, designated as the Z ring, at the septum site. Since inactivation of FtsZ or alteration of FtsZ assembly results in the inhibition of Z ring and septum formation, FtsZ is a promising target for new antimicrobial drug development. We screened 15,000 samples from extracts from marine microbial collection for FtsZ inhibitor. Consequently, 30 hit samples were obtained. These samples were fractionated by ethyl acetate and purified by reversed-ph … More ase HPLC. The structure of the purified sample was determined by NMR. Finally, we determined a novel compound with a strong bactericidal activity against MDR-TB.Screening of traditional herbal extracts for drug-resistant pathogens: It is believed that many traditional herbal tinctures had bactericidal activities. One hundred herbal tinctures were screened for the inhibition of bacterial growth of MRSA, VRE, and MDR-TB. A selection of the most active tinctures was crudely fractionated by solvent partition and purified by silica gel chromatography and TLC. Two highly active compounds were analogoues of acylated phloroglucinols and triketones. Therefore, a series of acylated phloroglucinols and triketones was synthesized and tested for activity against MRSA, VRE, and MDR-TB. A tetra-methylated triketone with a C12 side chain was the most active compound (MIC of around 1.0 μg/ml against MRSA) and was shown to stimulate oxygen consumption by resting cell suspensions, suggesting that the primary target was the cytoplasmic membrane. Less