Insight Into the Anti-staphylococcal Activity of JBC 1847 at Sub-Inhibitory Concentration

Frontiers in Microbiology

Bimal Jana¹  Lasse Saaby²  Kim Holmstrøm²  Søren Svenningsen³  Jørn B. Christensen³  Monica Monaco⁴  Viktoria Akkerboom⁵  Alexander W. Friedrich⁵  Artur J. Sabat⁵  Troels Ronco⁶  Maria F. Aragao⁶  Rikke H. Olsen⁶  Niccolo Biagi⁶  Marco Tinelli⁷  Janne K. Klitgaard⁸  Line H. Kappel⁹  Anders Permin^1,10 

[1] 0Department of Biology, Boston College, Chestnut Hill, MA, United States;Bioneer A/S, Hørsholm, Denmark;Department of Chemistry, Faculty of Science, University of Copenhagen, Copenhagen, Denmark;Department of Infectious Diseases, Istituto Superiore di Sanità, Rome, Italy;Department of Medical Microbiology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands;Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark;Division of Infectious and Tropical Diseases, Hospital of Lodi, Lodi, Italy;Research Unit of Clinical Microbiology, Institute of Clinical Research, University of Southern Denmark, Odense, Denmark;Research Unit of Molecular Microbiology, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark;Unibrains, Virum, Denmark;

关键词: phenothiazine derivative;    antimicrobial resistance;    mode of action;    RNA transcriptomics;    Gram-positive bacteria;   

DOI  :  10.3389/fmicb.2021.786173

来源: DOAJ

【 摘 要 】

Multidrug-resistant pathogens constitute a serious global issue and, therefore, novel antimicrobials with new modes of action are urgently needed. Here, we investigated the effect of a phenothiazine derivative (JBC 1847) with high antimicrobial activity on Staphylococcus aureus, using a wide range of in vitro assays, flow cytometry, and RNA transcriptomics. The flow cytometry results showed that JBC 1847 rapidly caused depolarization of the cell membrane, while the macromolecule synthesis inhibition assay showed that the synthesis rates of DNA, RNA, cell wall, and proteins, respectively, were strongly decreased. Transcriptome analysis of S. aureus exposed to sub-inhibitory concentrations of JBC 1847 identified a total of 78 downregulated genes, whereas not a single gene was found to be significantly upregulated. Most importantly, there was downregulation of genes involved in adenosintrifosfat (ATP)-dependent pathways, including histidine biosynthesis, which is likely to correlate with the observed lower level of intracellular ATP in JBC 1847–treated cells. Furthermore, we showed that JBC 1847 is bactericidal against both exponentially growing cells and cells in a stationary growth phase. In conclusion, our results showed that the antimicrobial properties of JBC 1847 were primarily caused by depolarization of the cell membrane resulting in dissipation of the proton motive force (PMF), whereby many essential bacterial processes are affected. JBC 1847 resulted in lowered intracellular levels of ATP followed by decreased macromolecule synthesis rate and downregulation of genes essential for the amino acid metabolism in S. aureus. Bacterial compensatory mechanisms for this proposed multi-target activity of JBC 1847 seem to be limited based on the observed very low frequency of resistance toward the compound.

【 授权许可】

Unknown