C109 is a potent but poorly soluble FtsZ inhibitor displaying promising activity against Burkholderia cenocepacia, a high-risk pathogen for cystic fibrosis (CF) sufferers. To harness C109 for inhalation, we developed nanocrystal-embedded dry powders for inhalation suspension consisting in C109 nanocrystals stabilized with D-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) embedded in hydroxypropyl-β-cyclodextrin (CD). The powders could be safely re-dispersed in water for in vitro aerosolization. Owing to the presence of a PEG shell, the rod shape and the peculiar aspect ratio, C109 nanocrystals were able to diffuse through artificial CF mucus. The promising technological features were completed by encouraging in vitro/in vivo effects. The formulations displayed no toxicity towards human bronchial epithelial cells and were active against planktonic and sessile B. cenocepacia strains. The efficacy of C109 nanosuspensions in combination with piperacillin was confirmed in a Galleria mellonella infection model, strengthening their potential for combined therapy of B. cenocepacia lung infections.
The emerging of multiple drug-resistant bacteria poses critical health threats worldwide. It is urgently needed to develop potent and safe antibacterial agents with novel bactericidal mechanisms to treat these infections. In this study, magnolol was identified as a potential bacterial cell division inhibitor by cell-based screening approach.
Project Team for Study of Nanotransportation System, Center for Medical Research and Development, Osaka Medical and Pharmaceutical University, 2-7 Daigaku-Machi, Takatsuki, Osaka, 569-8686, Japan.
Helicobacter pylori possesses an intrabacterial nanotransportation system (ibNoTS) for transporting VacA, CagA, and urease within the bacterial cytoplasm. This system is controlled by the extrabacterial environment. The transport routes of the system for VacA have not yet been studied in detail.
* Certain compounds showed strong inhibitory effects (13.8-90.1 µM) without harming human epithelial or red blood cells, with the most effective derivative undergoing further testing for its anti-biofilm properties and impact on methicillin-resistant bacteria.
* Analysis included a structure-activity relationship study to identify key structural features for antibacterial effectiveness, alongside molecular modeling that revealed how the active compound inhibits the FtsZ protein crucial for bacterial cell division.
Antimicrobial resistance (AMR) is a significant global threat, and the presence of resistance-determinant genes is one of the major driving forces behind it. The bacterial rod complex is an essential set of proteins that is crucial for cell survival due to its role in cell wall biogenesis and shape maintenance. Therefore, these proteins offer excellent potential as drug targets; however, compensatory mutations in nontarget genes render this complex nonessential.
The emergence of multidrug-resistant bacteria due to antibiotic abuse has created an urgent demand for new antimicrobial drugs.
FtsZ is a crucial protein in bacterial cell division and is becoming a promising target for the development of new antibiotics.
The paper reviews various natural and synthetic compounds that can inhibit FtsZ, highlighting its potential role in the discovery of novel antibacterial drugs.
