Antibacterial evaluation and mode of action study of BIMQ, a novel bacterial cell division inhibitor.

The worldwide spreading of antibiotic resistant bacteria is currently an extremely serious health risk and therefore to develop new antibiotics is an urgent need. In the present study, the antibacterial activity of a new indolyl quinolinium compound and its underline mechanism were investigated. The compound shows an outstanding antibacterial activity against the tested Gram-positive bacteria. The MIC values are in the range of 1-4 µg/mL. The elongation of B. subtilis cells indicates that the compound can inhibit cell division effectively. In addition, the biochemical studies prove that the compound is able to disrupt FtsZ polymerization effectively through a stimulatory mechanism. Furthermore, the compound can delay the development of drug resistance mutants.

Antibacterial activity of indolyl-quinolinium derivatives and study their mode of action.

Filamenting temperature-sensitive mutant Z (FtsZ) is recognized as a promising target for new antibiotics development because of its high conservatism and pivotal role in the bacteria cell division. The aromatic heterocyclic scaffold of indole is known showing merit medical functions in antiviral and antimicrobial. In the present study, a series of 1-methylquinolinium derivatives, which were integrated with an indole fragment at its 2-position and a variety of amino groups (cyclic or linear, mono- or di-amine) at the 4-position were synthesized and their antibacterial activities were evaluated. The results of antibacterial study show that the representative compounds can effectively inhibit the growth of testing strains including MRSA and VRE, with MIC values of 1-4 µg/mL by bactericidal mode. The mode of action assays revealed that c2 can effectively disrupt the rate of GTP hydrolysis and dynamic polymerization of FtsZ, and thus inhibits bacterial cell division and then causes bacterial cell death. In addition, the result of resistance generation experiment reveals that c2 is not likely to induce resistance in S. aureus.

Study of Benzofuroquinolinium Derivatives as a New Class of Potent Antibacterial Agent and the Mode of Inhibition Targeting FtsZ.

New generation of antibacterial agents are urgently needed in order to fight the emergence of multidrug-resistant bacteria. FtsZ is currently identified as a promising target for new types of antimicrobial compounds development because of its conservative characteristics and its essential role played in bacterial cell division. In the present study, the antibacterial activity of a series of benzofuroquinolinium derivatives was investigated. The results show that the compounds possess potent antibacterial activity against drug resistant pathogens including MRSA, VREF and NDM-1 Escherichia coli. Biological studies reveal that the compound is an effective inhibitor that is able to suppress FtsZ polymerization and GTPase activity and thus stopping the cell division and causing cell death. More importantly, this series of compounds shows low cytotoxicity on mammalian cells and therefore they could be new chemotypes for the development of new antibacterial agents targeting the cell-division protein FtsZ.

Antibacterial activity of 3-methylbenzo[d]thiazol-methylquinolinium derivatives and study of their action mechanism.

The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli. Among these derivatives, a compound bearing a 4-fluorophenyl group (A2) exhibited a superior antibacterial activity and its MICs to the drug-resistant strains are found lower than those of methicillin and vancomycin. The biological results suggest that these quinolinium derivatives can disrupt the GTPase activity and dynamic assembly of FtsZ, and thus inhibit bacterial cell division and then cause bacterial cell death. These compounds deserve further evaluation for the development of new antibacterial agents targeting FtsZ.

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. Both in vitro and in vivo results reveal that the compound is able to disrupt dynamic assembly of FtsZ and Z-ring formation effectively through the mechanism of stimulating FtsZ polymerization and impairing GTPase activity.