The current treatment of bacterial infections is challenged by a dramatic increase of multidrug-resistant (MDR) strains.
In addition to Gram-negative MDR pathogens cause infection, Gram-positive pathogens, such as Staphylococcus aureus, are the main reason for healthcare-associated infections.
Especially, methicillin-resistant S. aureus (MRSA) is difficult to treat and causes serious infection.
Bacterias become tolerant towards antibiotics due to a subpopulation of bacteria switches into a dormant state.
Moreover, bacterias in a dormant persister state build biofilms. however, many antibiotics cannot eradicate established biofilms. As a result, many persister cells cause a relapse of the infection and failure of treatment.
In this article, we will precisely introduce a potent kinase inhibitor for S. aureus, PK150.
Firstly, PK150 is against a panel of bacterias’ growth in a time-dependent manner. PK150 exhibits MICs of 0.3 µM, 0.3-1 µM and 0.3 µM for Gram-positive Methicillin-sensitive S. aureus (MSSA), Methicillin-resistant S. aureus (MRSA), Vancomycin intermediate S. aureus (VISA), respectively.
Nextly, in an independent assay format of Persister killing biological properties, PK150 can enhance cell membrane permeability. Additionally, PK150 disintegrates persister cells in a time- and dose-dependent manner. Furthermore, PK150 can significantly affect biofilm integrity by reducing colony-forming units. In staphylococcal biofilms, Pk150 treatment can cause an 80% reduction after 24 hours.
Signal peptidase IB (SpsB) is an essential membrane serine endopeptidase involves in the S. aureus protein secretion (Sec) pathway. In addition, SpsB activation can facilitate mature protein release after translocation in the membrane, and help to the killing of bacterial cells. PK150 can increase the secretion of SpsB-dependent proteins.
Lastly, in vivo.In Pathogen-free 9-week old female C57BL/6J mice, PK150 (20 mg/kg; p.o.) significantly reduces bacterial loads in the liver and heart by approximately 100-fold.
In Outbred male CD-1 mice, in a PK study, PK150 shows no obvious signs of toxicity in mice by oral administration (10 mg/kg or 20 mg/kg) and 10mg/kg intravenous administration. The oral l bioavailability is approximately 63%.
In conclusion, PK150 is potently against several pathogenic strains at submicromolar concentrations. And it exhibits optimal stability and oral bioavailability as well as a suitable in vivo efficacy.
Le P, et al. Nat Chem. 2019 Dec 16.